Bcs Classification Database

3/31/2019
  1. Bcs Classification Of Drugs
  2. Bcs Classification System Database

Classification of APIs according to the BCS According to the HHS-FDA definitions in the documents cited above, the four different categories possible for an API according to the BCS are.

  • Mar 9, 2006 - Dear friends Can someone provide information about existing BCS class databases or drug permeability databases?
  • Since the biopharmaceutics classification system (BCS) was introduced in 1995, it has had an increasing impact on regulatory practice. The BCS presented a new paradigm in bioequivalence, based on scientific principles.
Published online 2011 Aug 5. doi: 10.1208/s12248-011-9290-9
PMID: 21818695
This article has been cited by other articles in PMC.

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Supplementary Materials
12248_2011_9290_MOESM1_ESM.doc (5.5M)
12248_2011_9290_MOESM2_ESM.xlsx (275K)

Abstract

Here, we compile the Biopharmaceutics Drug Disposition Classification System (BDDCS) classification for 927 drugs, which include 30 active metabolites. Of the 897 parent drugs, 78.8% (707) are administered orally. Where the lowest measured solubility is found, this value is reported for 72.7% (513) of these orally administered drugs and a dose number is recorded. The measured values are reported for percent excreted unchanged in urine, LogP, and LogD7.4 when available. For all 927 compounds, the in silico parameters for predicted Log solubility in water, calculated LogP, polar surface area, and the number of hydrogen bond acceptors and hydrogen bond donors for the active moiety are also provided, thereby allowing comparison analyses for both in silico and experimentally measured values. We discuss the potential use of BDDCS to estimate the disposition characteristics of novel chemicals (new molecular entities) in the early stages of drug discovery and development. Transporter effects in the intestine and the liver are not clinically relevant for BDDCS class 1 drugs, but potentially can have a high impact for class 2 (efflux in the gut, and efflux and uptake in the liver) and class 3 (uptake and efflux in both gut and liver) drugs. A combination of high dose and low solubility is likely to cause BDDCS class 4 to be underpopulated in terms of approved drugs (N = 53 compared with over 200 each in classes 1–3). The influence of several measured and in silico parameters in the process of BDDCS category assignment is discussed in detail.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-011-9290-9) contains supplementary material, which is available to authorized users.

Key words: BDDCS, biowaiver, dose number, extent of metabolism, permeability rate

In 2005, Wu and Benet () introduced the Biopharmaceutics Drug Disposition Classification System (BDDCS). Wu and Benet recognized that there was a very strong correlation between the intestinal permeability rate and the extent of metabolism. For example, Benet et al. () noted that for the 29 drugs and endogenous substances for which human jejunal permeability rate measurements were available, there was an excellent correlation between these permeability rate measurements and the extent of drug metabolism in humans. Fourteen of the 16 drugs exhibiting human intestinal permeability rates greater than metoprolol were extensively metabolized, while 11 of 12 drugs showing permeability rates less than metoprolol were poorly metabolized. Two drugs showing disparity between the permeability rate and metabolism, cephalexin and losartan, exhibit permeability rates that differ by no more than 16% from metoprolol (). Since the coefficients of variation for the human permeability parameters range from 29% to 130%, these borderline compounds may in fact also have followed the correlation. The correlation between the extent of metabolism and human intestinal jejunal permeability was markedly better than that observed for intestinal jejunal permeability and partition coefficient by Takagi et al. (), who noted that Log P measured and calculated correctly predict high versus low permeability only about two thirds of the time. Wu and Benet () reasoned that it might be easier to utilize metabolism in assigning drug classification since it is difficult and expensive to determine human intestinal permeabilities and since it is also difficult to obtain quantitative mass balance measures that show ≥90% absorption, the FDA criterion for a biowaiver as defined in the FDA BCS Guidance (4), based on the work of Amidon et al. (). Therefore, in proposing the BDDCS classification system, Wu and Benet () substituted extensive and poor metabolism for high and low permeability in the BCS while utilizing the same criteria as the FDA for high and low solubility. That is, a high solubility compound at the highest marketed dose strength would be soluble in 250 mL of water over the pH range of 1–7.5 at 37°C. Using the BDDCS, Wu and Benet () classified 168 drugs based on the extent of metabolism and solubility.

BDDCS VERSUS BCS

Although BDDCS grew out of the FDA’s BCS Guidance (4), Wu and Benet () proposed BDDCS as a means to predict the drug disposition characteristics of novel chemicals (here, referred to as “new molecular entities”, NMEs) during the early stages of drug discovery and development. Such examples will be discussed below. Recently, Benet and Larregieu () reviewed the differences between BCS and BDDCS in terms of purpose and basis. The purpose of BCS is to facilitate biowaivers of in vivo bioequivalence studies for drugs that exhibit no significant intestinal absorption problems. In contrast, the purpose of BDDCS is to predict the drug disposition of NMEs as well as potential drug–drug interactions for NMEs and drugs on the market with respect to the intestine and liver. Very recently, a consensus paper with respect to BCS, BDDCS, and regulatory guidances has been published ().

Both BCS and BDDCS use the same criteria for solubility. Therefore, there is no difference in the basis between the two systems with respect to this parameter. As noted above, BDDCS predictions and classification are based on the intestinal permeability rate, not the extent of permeability. There is some ambiguity with respect to the basis for BCS, as reviewed by Benet and Larregieu (). The initial permeability studies of Amidon, Lennernäs, and colleagues (,), as summarized by Takagi et al. (), show a good correlation between human intestinal permeability rate and the extent of absorption, as detailed earlier in the first paragraph of this paper. However, the criterion listed in the FDA BCS Guidance (4) is “…a drug substance is considered to be highly permeable when the extent of absorption in humans is determined to be 90% or more of an administered dose based on a mass balance determination or in comparison to an intravenous reference dose” [emphasis added by the FDA]. Although permeability rate methods are listed in the FDA BCS Guidance (4), we are unaware of any drug that has been certified by the FDA as class 1 eligible for in vivo biowaiver where there is no confirmatory ≥90% absorption data. This ambiguity does not exist in the Guideline on the Investigation of Bioequivalence issued in 2010 by the European Medicines Agency (EMA), which only allows in vivo biowaivers based on the extent of absorption (9). This difference in the permeability basis between BCS and BDDCS is brought home in a recent publication by FDA scientists (). Chen and Yu () note that the FDA has classified as “highly permeable” a number of drugs where absorption is ≥90% in humans, but the measured permeability rates of these compounds are less than that for metoprolol (cefadroxil, cephradine, levofloxacin, loracarbef, ofloxacin, and sotalol), and in one case (pregabalin), the measured permeability rate is less than that for mannitol. As previously recognized (), BCS is influenced by transporter effects. For example, large amino acid transporter-1 (LAT-1) is expressed in Caco-2 cells (), and pregabalin is a LAT-1 substrate as noted in the package insert (12), which may explain this discrepancy. Since pregabalin is a zwitterion, its high oral bioavailability (≥90%) may be attributed to LAT-1 transport, an effect that is not taken into account by BCS. Thus, although in general drugs exhibiting high intestinal permeability rates show a high extent of absorption and a high extent of metabolism in both BCS and BDDCS, there are a number of drugs that could be classified as highly permeable in the BCS system based on absorption ≥90% but would be predicted to be poorly metabolized based on the low intestinal permeability rate, the basis for BDDCS classification. By evaluating metabolism, not permeability, BDDCS is not subject to variability due to transporter effects.

In general, classification of drugs between BCS and BDDCS only differ about 5–10%. However, for class 1 drugs where FDA has granted biowaivers, we estimate that the difference between BCS and BDDCS occurs for about 40% of drugs. We cannot make a more accurate estimate since the listing of all drugs granted biowaivers by the FDA is confidential. The percentage difference is high due to the ease in determining whether a drug is >90% absorbed (class 1 in BCS) when a drug is almost completely eliminated unchanged in the urine (class 3 in BDDCS).

BDDCS AND ITS USE

In 1995, Wu and Benet () reviewed 131 drugs that had been classified into the four BCS categories in the literature through the end of 1994. Ten of these drugs had been listed in different classes by different authors. Wu and Benet () recognized that the major route of elimination in humans for the great majority of high-permeability class 1 and class 2 drugs was metabolism, while the major route of elimination for the poorly permeable class 3 and class 4 drugs in humans was renal and biliary excretion of unchanged drug. They also noted that the major route of elimination via cytochrome P450 3A4 (CYP3A4) was only observed for the class 1 and class 2 drugs and that for the class 3 and class 4 drugs CYP3A4 was not a major contributor to elimination for any. Since the extent of metabolism is better characterized than the extent of absorption, for marketed drugs, Wu and Benet proposed that in BDDCS, drugs be categorized in terms of the extent of metabolism and solubility versus permeability rate and solubility (). This immediately eliminated the situation where drugs were classified in more than one class because of the uncertainty of permeability measures from study to study. The implication from the BDDCS for an NME is that if a surrogate measure of intestinal absorption rate is available, such as permeability rate through a Caco-2 cellular system, it would be possible to predict the major route of elimination for this new molecular entity in humans prior to its in vivo dosing to either animals or humans. Work is ongoing in our laboratory to determine the degree of accuracy in predicting BDDCS class for an NME based only on in vitro permeability measures prior to studies determining the extent of metabolism. Thus, Benet and Wu () proposed the BDDCS as shown in Fig. 1 with ≥70% metabolism being the cutoff for extensive metabolism. They also noted that there were relatively few drugs where the extent of metabolism was between 30% and 70% and that most drugs are either very highly metabolized or very poorly metabolized.

The Biopharmaceutics Drug Disposition Classification System (BDDCS) as proposed by Wu and Benet ()

Figure 2 summarizes the predictions from BDDCS related to the effects of enzymes and transporters in the gut and liver following oral dosing of drugs (,). For class 1, highly soluble—high permeability rate—extensively metabolized drugs, transporter effects in the intestine and the liver have no clinical impact. Even compounds like verapamil, which can be shown in certain cellular systems (e.g., MDR1-MDCK) to be a substrate for P-glycoprotein (P-gp), exhibit no clinically significant P-gp substrate effects in the gut and the liver. Thus, a major proposition of BDDCS is that although class 1 drugs may be shown in cellular systems to be substrates for transporters found in the intestine and the liver, this has no clinical relevance. However, a caution is in order here. At this time, BDDCS predictions only apply to the intestine and the liver since class 1 drugs could be substrates for transporters at the blood–brain barrier and in the kidney.

Transporter effects predicted by BDDCS following oral dosing

From Fig. 2, it can be seen that for class 2 drugs, efflux transporter effects will predominate in the intestines. Thus, transporter–enzyme interplay will be primarily important for class 2 compounds that are substrates for CYP3A and phase II gut enzymes (e.g., glucuronosyltransferases, sulfotransferases), where efflux transporter effects can control the access of the drug to the gut enzymes. BDDCS predicts that both uptake and efflux transporters can affect class 2 drug disposition in the liver. Thus, inhibition or induction of uptake hepatic transporters such as the SLCOs (OATPs) and the SLC22As (OATs and OCTs) as well as the drug efflux hepatic transporters ABCB1 (P-gp), ABCG2 (BCRP), and ABCCs (MRPs) can lead to changes in hepatic metabolism even when hepatic enzymes are unaffected.

BDDCS predicts that for class 3, highly soluble—poor permeability rate—poorly metabolized drugs, uptake transporters will be important for intestinal absorption and liver entry for these poorly permeable compounds (Fig. 2). However, once these drugs get into the enterocyte or the hepatocyte, efflux transporter effects can also occur. Similarly, uptake and efflux transporter effects would be expected for the poorly soluble class 4 compounds. Because they are numerically underrepresented, one might expect that class 4 drugs are more difficult to manage therapeutically, i.e., there are transporter effects just as in class 2, except these drugs are not significantly metabolized. As will be shown subsequently, plotting the maximum recommended therapeutic daily dose () versus BDDCS and looking at the “actives” (low dose) versus “inactives” (high dose, safer) revealed no such relationship. It is more likely that fewer drugs are represented in class 4 because of the combined negative characteristics of high dose and (comparatively) low solubility, which leads to high variability. Since the FDA criteria for solubility is measured in water, we suspect that the approved class 4 drugs have adequate solubility in the natural surfactant containing intestinal fluids.

Details and explications for the predictions in Fig. 2 have been presented in recent reviews from the Benet lab (,,). However, in large part, the predictions in Fig. 2 were based on clinical and experimental observations. That is, we are unaware of any clinically significant effects of the uptake and efflux transporters in the gut and liver on class 1 drugs, even when such drugs have been shown in cellular systems or other organs besides the gut and the liver to be substrates of the uptake and efflux transporters. These effects, however, might become relevant in overdosage situations, e.g., when combined with strong inhibitors of their respective metabolizing enzyme, when liver failure is manifest, or when accidentally overdosed. Similarly, we are unaware of the clinically significant effects of the uptake transporters in the gut for class 2 drugs even when these drugs are shown to be substrates of uptake transporters in the liver.

BDDCS also allows potential drug–drug interactions to be predicted (,). For class 1 drugs, only metabolic interactions need to be considered in the intestine and the liver. For class 2 drugs, metabolic, efflux transporter, and efflux transporter–enzyme interplay in the intestine must be taken into consideration, while in the liver, metabolic, uptake transporter, efflux transporter, and transporter–enzyme interplay (both uptake and efflux) can occur. For class 3 and class 4 drugs, uptake transporter, efflux transporter, and uptake–efflux transporter interplay will be of major importance.

BDDCS classification may also be useful in predicting the effect of high-fat meals on the extent of bioavailability (F) for an NME. In general, F for class 1 drugs is unaffected by high-fat meals; F is generally increased for class 2 drugs and generally decreased for class 3 drugs (). Custodio et al. () have observed that these findings would be the outcomes expected if a component of high-fat meals inhibited both the uptake and efflux transporters. However, even if this were true, high-fat meals would be expected to have many other effects than inhibiting transporters. We estimate that the predicted effect of high-fat meals on F is only correct about 70% of the time.

CAUTION

It is surprising that such a simple four-category process as indicated in Fig. 2 works so well in predicting drug disposition, transporter–enzyme effects, and drug interactions. It is obvious, however, that this simple four-category system will not predict every interaction. BDDCS does not propose that every drug in the class will be substrates or not substrates for the uptake and efflux transporters. Rather, BDDCS helps prioritize what interactions should and should not be investigated. For example, the class 2 drug felodipine has been shown not to be affected by the intestinal or hepatic efflux transporters (). Recently, our laboratory has shown the importance in humans of hepatic uptake transporters for the drugs atorvastatin and glyburide (,). These interactions were predicted based on cellular, isolated organ, and animal studies (–). Even when such preliminary studies confirm BDDCS predictions, this may not always be the case. Warfarin is a class 2 drug and, thus according to BDDCS, may be a substrate for a hepatic uptake transporter. In vitro studies in human and rat hepatocytes showed that rifampin would decrease warfarin metabolism by 30% (), a similar extent to that found for our in vitro results with glyburide (). However, our recently published study examining the effects of a single dose of rifampin on the pharmacokinetics of warfarin in healthy volunteers showed that OATP uptake in vivo in humans was not clinically significant for warfarin (). Similarly, although warfarin appears to be both a substrate and inhibitor of liver-bound P-gp (26), this has not been regarded as clinically significant; one P-gp haplotype, however, is clearly associated with low-dose warfarin in a 201 patient sample (). This emphasizes again the caution that BDDCS only predicts with respect to transporters what might occur, but not that the effect will always occur. Furthermore, our example above () reinforces the well-recognized concept that observations in cellular systems and animal models must be tested in vivo in humans before the significance of the effect is assumed.

WHY DID WE PREPARE THIS PAPER?

Wu and Benet () recognized that the FDA’s BCS approach (4) held the potential for predicting the drug disposition characteristics and drug interactions for NMEs as well as for drugs on the market. The use of BDDCS in the area of systems chemical biology () has been previously outlined (), and computational models to assign BDDCS class from molecular structure have been proposed (). However, to test the usefulness of BDDCS, to examine patterns within the BDDCS classes and among them, and to gain further perspectives, it is necessary to compile a large database, at least with respect to drugs that have reached the market. Since BDDCS makes predictions related to hepatic elimination in addition to intestinal absorption, such a database should include as many drugs as possible where systemic concentrations are relevant. Thus, approximately one quarter of the drugs categorized here are administered exclusively by non-oral routes. We also felt strongly that the information provided in the database should be based, where available, not only on the in silico predictions of those parameters but also on experimental values. We noted that many of the solubility values used in BCS analyses are frequently in silico predictions of solubility. For example, in the often quoted paper of Willmann et al. () describing a physiological model for the estimation of the fraction dose absorbed in humans, the measured solubility values were only included for only 22 of the 126 drugs evaluated. The solubility for the great majority of the drugs utilized in the Willmann et al. () analysis came from the compilation of Zhao et al. (). These latter workers evaluated human intestinal absorption data for 241 drugs (). Of the 241 drugs, Zhao et al. compared the experimental results for 26 of the compounds with the predicted solubility utilizing the method of Meylen et al. (33) based on octanol water partition coefficients. For these 26 drugs, the measured versus calculated solubility differs by a factor of 5.7 ± 6.0-fold, the greatest difference being 23-fold. Thus, at present, in silico methodologies for aqueous solubility prediction are not sufficiently accurate for the BDDCS analysis not only due to the inherent limitations of such methods but also to its definition, i.e., BDDCS solubility categorization depends on the maximum strength dose and the effect of pH. Experimental solubility values were included in this compilation wherever they could be found in the literature (577 drugs). Qualitative evaluations such as “practically insoluble in water,” which relate to upper limits, and “highly soluble in water” were used in the absence of published solubility values from a reliable source and were the basis of the BDDCS assignment when no measured value is listed in the table.

Frequently, large compilations such as the ones presented here are carried out with the assistance of graduate students, postdoctoral fellows, and auxiliary personnel. In our experience, this can lead to unevenness in the quality of the data presented in the table. For each of the drugs listed here, decisions concerning the experimental values to be listed and classification assigned were made during the multiple joint meetings of Drs. Benet and Oprea between February 2007 and February 2011. Then, Dr. Broccatelli captured potential errors by cross-checking many references. Therefore, if there are errors in the parameters or in the assignments, this can only be attributable to the authors.

MEASURED PARAMETERS (IN ORDER OF DIFFICULTY)

Solubility

There are a number of issues concerning the choice of the high versus low solubility criteria and which representative experimental values should be listed. The high solubility criterion that the highest dose strength on the market is soluble in 250 mL or less of water over the pH range 1–7.5 at 37°C was an arbitrary decision made by Amidon et al. () and incorporated into the regulatory Guidances (4,9). Wu and Benet () found that this cutoff criterion in BCS appeared to work well for BDDCS, and thus, we have continued to use this arbitrary, discriminatory criterion. The FDA criteria (4) require the solubility measurements to be made in water, not simulated intestinal fluid containing a surfactant, and the solubility values listed in the table are values in water. Furthermore, the FDA criteria evaluate the cutoff between high and low solubility using the value for the lowest solubility over the pH range 1–7.5 (realistically measured at pH 1.2, 4.5, and 6.8 as indicated in the FDA Guidance). Furthermore, the solubility is to be measured at 37°C. The values in Tables I, ,II,II, III, ,IV,IV, and andVV are the authors’ best recommendation based on experimental literature data for the lowest solubility under the conditions listed above. The solubility criteria over the pH range 1–7.5 can create marked differences from compilation to compilation for drugs that are salts. For example, one may find in the package insert for atazanavir sulfate that the drug “is slightly soluble in water (4–5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9.” Reporting this solubility would lead to the assignment of atazanavir sulfate as a class 1 drug in BCS and BDDCS. However, it is known that atazanavir, as for almost all the protease inhibitors, exhibits very poor solubility in solutions at pH above 5.5, although these solubilities are not reported. Therefore, we list atazanavir sulfate as a class 2 drug and no specific solubility is listed in Table II. Another example of a basic drug is imatinib mesylate (and other kinase inhibitors) where the package insert states “Imatinib mesylate is soluble in aqueous buffers ≤pH 5.5 [a published value of 200 mg/mL can be found] but is very slightly soluble to insoluble in neutral/alkaline aqueous buffers.” Therefore, we list this drug in Table II as class 2 with a solubility of 1 mg/mL, determined at pH 7.4. Similar variances can occur for acidic drugs where solubility may be very low at pH 1. This concern that the pH range maybe too restrictive has been addressed () and explicated () previously for acidic drugs. Individual references are not given for the solubility values because in many cases the values in the tables are the authors’ consensus view of the appropriate value based on a number of experimental results as discussed above. This is a technique followed by Dr. Benet when he first introduced the table of pharmacokinetic parameters in Goodman and Gilman and represents a decision of the two senior authors alone in reviewing all of the literature data that they could find. A single solubility value is given in the five tables in milligrams per milliliter.

Table I

Measured and In Silico Data for 351 BDDCS Class 1 Drugs

Generic nameMaximum strength dose valueMaximum strength dose unitFormulationRouteMeasured solubility (mg/mL)Dose number% Excreted unchanged in urineMW drugMeasured LogS molarMeasured LogPMeasured LogD74minVSLgS 3–7.5CLogPHBAHBDPSA
Abacavir sulfate300mgTabletsOral770.021.2286.34−0.571.201.20−3.070.816395.80
Acarbose100mgTabletsOral1645.62−8.833.30−6.661914351.80
Acebutolol hydrochloride400mgCapsulesOral10336.431.710.19−1.461.715397.05
Acetaminophen; paracetamol1000mgTabletsOral23.70.23151.17−0.800.200.40−1.660.492255.41
Acetohexamide500mgTabletsOral3.430.6324.40−1.982.44−0.36−3.132.2542103.22
Acetylsalicylic acid; aspirin500mgTabletsOral100.21.4180.16−1.261.19−2.57−0.941.023168.21
Adenosine3mg/mLSolutionInjection (i.v.)50267.25−1.73−0.98−1.10−1.37−2.1684135.44
Alfacalcidol1μgCapsulesOral8400.65−5.868.242245.12
Alfentanil0.5mg/mLSolutionInjection (i.v.)0.5416.532.162.10−4.122.136077.73
Alfuzosin10mgTabletsOral11389.46−1.18−3.802.5582108.88
Aliskiren300mgTabletsOral3500.00325551.77−0.202.45−3.093.5174156.62
Alosetron1mgTabletsOral610.000076294.36−0.68−3.261.742144.23
Alprazolam2mgTabletsOral0.0730.120308.77−3.632.121.26−3.682.563033.27
Alprenolol200mgTabletsOral500.020.5249.36−0.703.101.34−0.862.653246.24
Ambrisentan10mgTabletsOral0.060.75376.46−3.80−3.353.335170.11
Ambroxol30mgTabletsOral10.90.018364.08−1.52−2.442.663364.50
Amifostine5mg/mLSolutionInjection (i.v.)0.69214.22−1.043.12−1.8554106.66
Aminophenazone; aminopyrine300mgTabletsOral55.550.02231.30−0.621.00−2.231.043026.79
Amitriptyline hydrochloride150mgTabletsOral10000.00061277.410.504.922.95−2.294.85101.18
Amlodipine10mgTabletsOral10408.893.001.68−1.793.4352105.47
Amoxapine150mgTabletsOral313.79−2.433.413134.47
Amsacrine33.33mg/mLSolutionInjection (i.v.)10393.47−1.374.695285.11
Anastrozole1mgTabletsOral0.50.00810293.37−2.77−3.601.294061.36
Anhydrovinblastine; anhydrovincaleukoblastine1mg/mLSolutionInjection (i.v.)100.00040.5792.98−1.903.703.69−7.126.1182130.05
Antipyrine; phenazone500mgTabletsOral17000.0010.5188.230.960.28−1.790.202022.02
Apomorphine2.56mgTabletsInjection (s.c.)200.00050.3267.33−1.132.30−2.732.493246.92
Asenapine10mgTabletsOral1285.78−2.414.581010.59
Atomoxetine60mgCapsulesOral27.80.0091.5255.36−0.96−1.143.942123.68
Azathioprine100mgTabletsOral100.041277.27−1.440.100.02−2.720.516199.66
Bambuterol20mgTabletsOral330.0020367.45−1.051.50−2.58−1.560.564294.24
Benazepril40mgTabletsOral780.0020.5424.50−0.741.10−1.841.8252101.61
Bendamustine5mg/mLSolutionInjection (i.v.)1358.27−0.832.764169.78
Benidipine8mgTabletsOral1.90.021535.65−2.45−5.697.4100112.85
Benserazide50mgTabletsOral1257.252.13−2.9077169.84
Benznidazole100mgTabletsOral0.41.0260.25−2.81−2.650.904187.81
Bepridil400mgTabletsOral50.30.5366.55−1.872.00−4.296.203010.84
Beraprost0.04mgTabletsOral190.000008398.50−1.32−4.642.045395.05
Betamethasone5mgTabletsOral0.0660.34.8392.47−3.771.941.94−3.611.7953104.22
Betaxolol20mgTabletsOral0.4510.215307.44−2.832.810.55−1.662.324255.03
Bimatoprost0.30mg/mLSolutionOphthalmic0.8415.58−2.72−5.441.7544100.52
Biperiden2mgTabletsOral10.008311.47−2.494.25−1.934.942123.73
Bopindolol2mgTabletsOral3.30.0020380.49−2.064.22−3.924.983264.71
Bortezomib1mg/mLSolutionInjection (i.v.)3.3384.25−2.07−4.090.7864151.53
Brimonidine2mg/mLSolutionOphthalmic1.510292.14−2.290.78−2.001.495258.94
Bromazepam6mgTabletsOral0.170.1316.16−3.272.051.54−3.471.703152.40
Bromocriptine5mgCapsulesOral0.80.032654.61−2.914.59−6.806.5863118.24
Bromperidol10mgTabletsOral0.090.40.5420.33−3.672.743.34−3.844.003142.01
Budesonide3mgCapsulesOral0.020.60430.55−4.333.202.70−4.712.916299.25
Buflomedil hydrochloride300mgTabletsOral23.6307.39−0.75−1.232.935046.76
Bupivacaine5mg/mLSolutionInjection (epidural)0.172288.44−3.233.41−3.533.692133.72
Buprenorphine hydrochloride8mgTabletsOral170.0021467.65−1.474.98−3.583.995264.50
Bupropion100mgTabletsOral3120.0010.5239.750.113.27−1.993.212132.84
Busulfan (busulphan)2mgTabletsOral0.10.081246.30−3.39−0.52−0.52−1.20−0.594092.04
Butabarbital100mgTabletsOral1212.251.651.45−2.421.583283.96
Butalbital50mgTabletsOral3.6224.26−2.741.633283.96
Butorphanol5mgTabletsOral20.012327.47−2.212.26−2.403.733246.61
Caffeine65mgCapletsOral21.50.011194.19−0.96−0.07−0.07−1.95−0.043048.50
Capecitabine500mgTabletsOral260.083359.36−1.14−3.450.8463124.33
Caprylidene20000mgPowderOral0470.70−7.699.973081.19
Carbidopa25mgTabletsOral2.50.045.3226.23−1.961.33−0.4565132.39
Carmustine7.70mgImplantTopical (skin, membranes)3.80.0080.5214.05−1.751.531.53−2.501.322169.78
Caspofungin acetate6.48mg/mLSolutionInjection (i.v.)1.41093.34−3.18−2.951816454.42
Cefoperazone2000mgPowderInjection (i.v.)29645.68−0.74−2.12−3.47−0.22114227.75
Cerivastatin0.8mgTabletsOral1950.0000224459.56−0.37−2.003.5663104.98
Cetrorelix3mg/mLSolutionInjection (s.c.)831431.07−2.25−7.00−0.401817543.33
Cevimeline30mgCapsulesOral13.5199.32−1.321.14209.97
Chloral hydrate500mgCapsulesOral83000.0002165.401.700.991.61−0.770.722245.12
Chlorambucil2mgTabletsOral120.00070.5304.22−1.403.251.59−0.273.633141.70
Chloramphenicol250mgCapsulesOral2.50.45323.13−2.111.141.00−2.791.2853122.11
Chlordiazepoxide25mgCapsulesOral20.050.5299.76−2.182.442.19−2.653.793145.94
Chlormethiazole; clomethiazole192mgCapsulesOral100.080.05161.65−1.212.122.12−1.801.681010.24
Chlorpheniramine4mgTabletsOral10274.803.381.38−1.573.152011.42
Chlorpromazine200mgTabletsOral4000.0020.5318.870.105.412.82−2.695.30201.75
Cilazapril5mgTabletsOral10.020417.51−2.62−2.25−0.781.4762106.36
Cisplatin1mg/mLSolutionInjection (i.v.)2.532.3300.06−2.07−2.53−1.680275.29
Clemastine2mgTabletsOral2.30.0035343.90−2.175.493.04−2.565.45209.97
Clindamycin hydrochloride hydrate300mgCapsulesOral400.0313424.99−1.082.16−2.992.5764110.49
Clobazam10mgTabletsOral0.1880.2300.75−3.202.121.90−3.632.442037.99
Clofibric acidActive metabolite455.7214.65−0.682.57−1.13−1.632.823149.94
Clomiphene citrate50mgTabletsOral1.110.28405.97−2.736.70−4.247.152010.28
Clomipramine75mgTabletsOral314.865.192.76−2.565.92201.75
Clonazepam2mgTabletsOral0.10.080.5315.72−3.502.412.41−3.962.384186.30
Clorazepate15mgTabletsOral0.5314.73−1.13−2.362.514282.98
Cocaine0.1mg/mLSolutionTopical (nasal)1.61303.36−2.282.302.30−2.852.573055.30
Codeine monohydrate60mgTabletsOral4350.00060.1299.370.141.190.21−1.400.984141.94
Colchicine0.6mgTabletsOral450.00005399.45−0.951.301.03−3.901.206187.54
Cortisone25mgTabletsOral0.280.4360.45−3.111.471.47−3.521.305299.93
Cyanocobalamin (vitamin B12)5mgTabletsOral12.50.0020.51355.40−2.040.05−1.36179492.69
Cyclizine50mgTabletsOral8.70.020.5266.39−1.49−2.973.80202.35
Cyclobenzaprine10mgTabletsOral2000.00020.5275.40−0.14−2.585.10101.18
Cyclophosphamide50mgTabletsOral400.0056.5261.09−0.810.630.63−1.920.802144.31
Cyproheptadine4mgTabletsOral3.6360.0040.5287.41−1.904.69−3.195.30101.18
Cytarabine20mg/mLSolutionInjection (i.v.)11243.22−2.51−2.24−0.60−2.2074133.23
Dabigatran etexilate110mgCapsulesOral1.80.20627.75−2.543.80−7.744.1382146.19
Dantrolene100mgCapsulesOral20.25314.26−2.201.700.77−3.441.6351118.74
Darifenacin15mgTabletsOral12.5426.56−3.743.623156.52
Debrisoquine20mgTabletsOral290.00312175.24−0.780.75−2.962.590.903252.16
DesalkylflurazepamActive metabolite0.5288.712.702.78−3.782.812142.15
Desipramine200mgTabletsOral2266.394.901.40−0.804.472115.14
Desmethyldiazepam (nordazepam)10mgTabletsOral0.0570.70.5270.72−3.682.932.93−3.693.022142.15
Desogestrel1.5mgTabletsOral0.320.020310.48−2.99−4.865.681122.56
Dexamethasone0.75mgTabletsOral0.0920.032.6392.47−3.631.941.83−3.651.7953104.22
Dexmethylphenidate10mgTabletsOral0.5233.311.80−0.28−1.612.562141.64
Dextromethorphan hydrobromide60mgTabletsOral150.020.19271.41−1.26−1.353.952010.28
Dezocine15mg/mLSolutionInjection (i.v.)201245.37−1.091.12−0.653.722250.84
Diazepam10mgTabletsOral0.0570.70.5284.75−3.702.822.99−3.752.962028.76
Diclofenac50mgTabletsOral90.020.5296.16−1.524.511.13−3.434.733254.80
Dihydroquinidine; hydroquinidine300mgTabletsOral11.10.118326.44−1.513.441.82−2.613.276343.08
Dilevalol50mgTabletsOral162.5328.41−1.313.091.07−2.092.5044106.25
Diltiazem120mgCapsulesOral2414.532.702.22−3.773.654056.49
Diphenhydramine50mgCapsulesOral10000.00022255.360.593.271.61−1.843.45209.97
Dobutamine hydrochloride12.5mg/mLSolutionInjection (i.v.)0.1301.39−1.852.434483.19
Dolasetron100mgTabletsOral0324.38−1.962.343160.48
Dosulepin; dothiepin75mgTabletsOral5005295.450.234.492.76−2.264.53101.18
Doxazosin8mgTabletsOral451.490.60−4.553.5391104.90
Doxepin100mgCapsulesOral0279.394.292.37−2.304.092010.28
Doxorubicin2mg/mLSolutionInjection (i.v.)103.5543.53−1.741.271.27−3.740.32126222.89
Duloxetine hydrochloride67.3mgCapsulesOral0297.42−2.224.262123.68
Eletriptan hydrobromide40mgTabletsOral40.045382.53−1.981.10−2.303.363151.90
Enalapril20mgTabletsOral250.00310376.46−1.18−0.670.6752101.91
Enfuvirtide90mg/mLSolutionInjection (i.m.)100004491.98−0.6567632095.89
Epirubicin2mg/mLSolutionInjection (i.v.)9.5543.531.270.46−3.770.32126222.89
Ergonovine; ergometrine0.2mgTabletsOral100.00008325.41−1.51−3.071.233370.55
Ergotamine tartrate2mgTabletsOral20.004581.68−2.823.692.85−2.744.6663118.24
Escitalopram20mgTabletsOral8324.40−2.943.133028.67
Esmolol10mg/mLSolutionInjection (i.v.)200.5295.38−1.17−0.801.724273.30
Esomeprazole magnesium20mgTabletsOral0.50.20.5345.42−2.842.23−3.692.575171.04
Estradiol2mgTabletsOral0.090.090.5272.39−3.484.01−3.903.782245.43
Eszopiclone3mgTabletsOral5388.82−2.821.256079.29
Ethanol62mg/mLSolutionOral2.546.07−0.31−0.311.06−0.241122.56
Ethinylestradiol1mgTabletsOral3296.413.673.67−4.163.862245.43
Ethosuximide250mgCapsulesOral39.20.0325141.17−0.560.381.13−1.240.402151.12
Etonogestrel157μgTablets (and 68 mg implant s.c)Topical (skin. membranes)0.510.0010.1324.47−2.80−4.615.682122.56
Everolimus1mgTabletsOral0.010.40958.25−4.98−8.687.10133212.97
Exenatide0.25mg/mLSolutionInjection (s.c.)254186.66−2.221.6167581923.78
Famciclovir500mgTabletsOral2500.0080321.34−0.11−2.790.0961113.10
Fentanyl1.6mgLozengeOral250.00038336.48−1.134.052.92−3.653.622020.32
Fesoterodine8mgTabletsOral2560.00010411.59−0.21−1.834.363151.11
Finasteride5mgTabletsOral0.0430.50.5372.56−3.943.033.03−4.383.012265.69
FludarabineActive metabolite24285.24−0.80−2.32−1.68−2.0184135.44
Fludarabine 5′-monophosphate10mgTabletsOral3.530.01365.22−2.010.64−3.0784185.94
Fludrocortisone acetate0.1mgTabletsOral0.140.0031422.50−3.481.671.67−4.001.5452104.22
Flumazenil0.1mg/mLSolutionInjection (i.v.)0.1280.5303.30−3.371.000.87−3.341.293057.02
Flunitrazepam1mgTabletsOral0.0041.00.5313.29−4.892.062.06−3.531.784072.91
Fluorouracil25mg/mLSolutionInjection (i.v.)12.25130.08−1.03−0.89−0.89−0.62−0.582264.48
Fluoxetine20mgCapsulesOral15.20.0051.25309.33−1.314.051.95−1.194.572123.68
Flurazepam30mgCapsulesOral5000.00020.1387.890.113.942.35−3.524.223029.93
Fluvastatin sodium40mgCapsulesOral500.0031.5411.48−0.923.80−4.004.054386.52
Fluvoxamine100mgTabletsOral14.8690.032318.34−1.331.121.21−1.683.324158.37
Formoterol fumarate12μg/inhalationPowderTopical (aerosol)0.660.000078344.41−2.72−2.001.2654101.65
Fosfluconazole100mgTabletsOral386.260.952.41−0.7872120.98
Frovatriptan2.5mgTabletsOral6243.310.420.722374.79
Galantamine12mgTabletsOral100.00520287.36−1.46−1.091.034141.94
Gemcitabine hydrochloride40mg/mLSolutionInjection (i.v.)158263.20−1.24−0.97−0.7163110.67
Glibornuride25mgTabletsOral0.20.50.5366.48−3.262.603.53−3.753.7043107.50
Goserelin10.8mgImplantInjection (s.c.)201269.44−5.55−2.861818537.10
Granisetron1mgTabletsOral1000.0000411312.42−0.49−0.85−1.161.723147.74
Guanabenz16mgTabletsOral110.006231.09−1.320.12−1.382.984378.44
Heparin; enoxaparin20mg/mLSolution (10,000 units/mL)Injection (i.v.)500.51134.94−1.36−3.81−9.693315662.73
Hexobarbital250mgTabletsOral6400.0020.5236.270.431.981.98−2.811.633170.56
Hydralazine hydrochloride100mgTabletsOral44.20.0098160.18−0.651.000.56−1.290.664267.97
Hydrocodone10mgTabletsOral62.50.000610.2299.37−0.681.273.38−1.251.134037.66
Hydrocortisone; cortisol20mgTabletsOral0.420.2362.47−2.941.611.37−3.481.7053104.22
Hydromorphone8mgTabletsOral100.0036285.35−1.46−1.060.724151.42
Hydroxychloroquine sulfate200mgTabletsOral2000.00427335.88−0.231.72−1.644.124248.25
Hydroxyzine100mgTabletsOral7000.00060.1374.910.273.502.37−3.764.004133.70
Ibutilide0.1mg/mLSolutionInjection (i.v.)1007384.59−0.58−2.013.784275.53
Idarubicin1mg/mLSolutionInjection (i.v.)3497.511.63−3.810.90105191.23
Ifosfamide50mg/mLSolutionInjection (i.v.)10010261.09−0.420.860.86−2.400.922144.31
Iloprost5μg/inhalationSolutionTopical (aerosol)10.000020360.50−2.562.970.46−4.402.714385.95
Imidapril10mgTabletsOral5405.45−0.681.5362121.36
Imipramine50mgTabletsOral1.5280.424.802.20−2.045.04201.75
Imiquimod50mg/gCreamTopical (skin. membranes)0.61240.31−2.60−2.713.243148.73
Inamrinone; amrinone lactate0.25mg/mLSolutionInjection (i.v.)0.925187.20−2.49−0.70−1.89−0.693270.15
Indapamide2.5mgTabletsOral0.590.027365.84−2.792.09−3.702.9642102.49
Irinotecan20mg/mLSolutionInjection (i.v.)1016.7586.69−1.77−3.792.7361108.44
Isoniazid300mgTabletsOral1530.0087137.140.05−0.70−1.14−0.67−0.673274.33
Isosorbide 2-mononitrate10mgTabletsOral1.10.04191.14−2.24−0.40−0.40−0.83−0.666196.60
Isosorbide 5-mononitrate20mgTabletsOral1.10.072.5191.14−2.24−0.40−0.15−0.88−0.666196.60
Isosorbide dinitrate40mgTabletsOral1.0890.1236.14−2.341.311.31−2.150.2280130.49
Ivabradine7.5mgTabletsOral4468.60−3.333.976057.04
Ivermectin3mgTabletsOral40.003875.12−2.346.82−8.485.39133173.88
Ketamine100mg/mLSolutionInjection (i.v.)2004237.73−0.082.182.09−1.352.932132.84
Labetalol300mgTabletsOral160.082.5328.41−1.311.331.08−2.142.5044106.25
Letrozole2.5mgTabletsOral0.0410.23.9285.31−3.84−4.711.244061.36
Leuprolide45mg/mLSolutionInjection (s.c.)25021209.43−0.68−5.36−0.991616464.21
Levamisole50mgTabletsOral204.301.841.16−1.621.842010.79
Levobupivacaine7.5mg/mLSolutionInjection (epidural)0.170.20.5288.44−3.233.212.66−3.533.692133.72
Levodopa250mgTabletsOral1.650.60.5197.19−2.08−2.74−2.391.48−2.8254114.54
Lidocaine20mg/mLSolutionInjection (i.v.)3.588234.34−1.822.441.88−2.091.952133.72
Linezolid600mgTabletsOral80.330337.35−1.621.80−3.420.175170.45
Liraglutide6mg/mLSolutionInjection (s.c.)63751.2959541675.18
Lorazepam2mgTabletsOral0.080.10.5321.17−3.602.392.39−3.962.373264.71
Lorcainide hydrochloride100mgTabletsOral2.40.21370.93−2.194.852.84−2.884.482020.32
Maprotiline75mgTabletsOral3.1340.103277.41−1.954.851.43−1.174.521114.57
Maraviroc300mgTabletsOral8513.68−3.533.264157.98
Melatonin5mgTabletsOral0.10.2232.28−3.37−2.781.032255.92
Melphalan2mgTabletsOral0.10.0812305.21−3.48−0.11−0.39−0.214269.67
Meperidine; pethidine100mgTabletsOral3.220.113247.34−1.892.721.44−1.652.232028.24
Mepivacaine20mg/mLSolutionInjection (epidural)2.45246.36−2.011.951.75−2.742.102133.72
Meprobamate400mgTabletsOral3.40.5218.25−1.810.700.70−1.530.9222110.07
Mesna400mgTabletsOral142.201.69−1.553259.79
Methadone10mgTabletsOral1200.000324309.46−0.413.932.07−2.464.172019.45
Methohexital10mg/mLSolutionInjection (i.v.)1000.5262.31−0.422.30−3.131.813170.56
Methylergonovine0.2mgTabletsOral339.44−3.301.763370.55
Methylphenidate20mgTabletsOral233.311.80−0.28−1.752.562141.64
Methylprednisolone32mgTabletsOral0.32360.44.9374.48−3.062.18−3.871.7453104.22
Metoprolol100mgTabletsOral10000.000410267.370.571.880.16−0.811.494255.03
Metronidazole500mgTabletsOral100.210171.16−1.23−0.020.14−1.43−0.464177.52
Mexiletine250mgCapsulesOral9.5179.262.152.15−0.122.572137.08
Mianserin60mgTabletsOral3.40.075264.37−1.894.242.52−2.733.76202.05
Micafungin sodium10mg/mLSolutionInjection (i.v.)11270.30−7.93−2.592216554.51
Midazolam hydrochloride2mg/mLSyrupOral10.35.6325.78−1.553.271.53−3.923.422020.12
Minocycline hydrochloride100mgCapsulesOral500.00811457.49−0.960.050.042.530.1995175.38
Minoxidil10mgTabletsOral2.20.0210209.25−1.981.241.38−1.86−0.725289.15
Mirtazapine45mgTabletsOral0.50.42265.36−2.72−2.312.813012.29
Misoprostol0.2mgTabletsOral0.5382.552.91−5.013.074290.45
Molindone50mgTabletsOral2276.38−1.772.573142.21
Morphine hydrochloride30mgCapsulesOral57.140.0024285.35−0.750.891.03−1.260.574255.71
Nafarelin0.2mg/actuationSolutionTopical (nasal)10.000831322.50−3.12−5.45−1.221717510.46
Nalbuphine hydrochloride20mg/mLSolutionInjection (i.v.)35.54357.45−1.00−2.411.395378.27
Nalmefene hydrochloride1mg/mLSolutionInjection (i.v.)1249.6339.44−0.44−1.13−2.872.644255.71
Naloxone2mgTabletsOral0327.382.091.28−2.140.165273.98
Naltrexone100mgTabletsOral1000.0041341.41−0.531.920.90−2.100.365273.98
Nefopam30mgTabletsOral340.0043253.35−0.873.00−2.392.91209.97
Niacin; nicotinic acid1000mgCapsulesOral16.660.2123.11−0.870.36−2.87−0.050.803151.07
Niacinamide; nicotinamide750mgTabletsOral10000.003122.130.91−1.010.802156.49
Nicardipine30mgCapsulesOral7.90.020479.54−1.783.82−4.965.2361114.03
Nicorandil20mgTabletsOral4.20.020.5211.18−1.700.72−1.980.755199.54
Nicotine4mgTablets (as chewing gum)Oral16.7162.241.170.43−0.250.882011.42
Nitroglycerin0.4mgTabletsSublingual0.80.0020.5227.09−2.451.621.62−2.681.7690169.35
Norethindrone0.35mgTabletsOral0.010.12298.43−4.472.972.97−3.972.782140.83
Norgestimate0.25mgTabletsOral0.020.050369.51−4.273.60−5.175.063162.44
Norgestrel0.5mgTabletsOral0.0021.00312.46−5.193.60−4.383.312140.83
NortilidineActive metabolite3259.35−2.483.162141.64
Nortriptyline75mgCapsulesOral2263.394.041.69−1.224.321114.57
Octreotide acetate1mg/mLSolutionInjection (i.v.)321019.26−4.532.511213367.50
Olmesartan medoxomil40mgTabletsOral20.080558.60−2.45−3.532.9182150.96
Omeprazole40mgTabletsOral0.50.30345.42−2.842.232.23−3.692.575171.04
Ondansetron8mgTabletsOral5.70.0065293.37−1.712.12−3.182.722029.66
Orphenadrine100mgTabletsOral100.048269.39−1.433.772.78−2.183.90209.97
Oseltamivir phosphate75mgCapsulesOral2312.41−2.362.134296.67
Oxaliplatin5mg/mLSolutionInjection (i.v.)6395.29−1.823.130.782248.49
Oxprenolol80mgTabletsOral30.860.013265.36−0.932.100.18−0.802.094255.34
Oxybutynin hydrochloride15mgTabletsOral0.80.080.5357.50−2.69−4.234.873150.80
Oxycodone80mgTabletsOral1000.00319315.37−0.500.211.65−1.64−0.045160.22
Oxymorphone40mgTabletsOral240.0071.9301.35−1.100.900.98−1.39−0.485273.98
p-Aminosalicylic acid (PAS)1200mgTabletsOral142.850.032153.14−0.030.89−0.321.064391.37
Pantoprazole sodium40mgTabletsOral0383.38−3.452.116180.15
Paroxetine40mgTabletsOral5.40.032329.37−1.791.19−1.974.244141.89
Pefloxacin400mgTabletsOral11.40.112333.37−1.470.270.15−0.61−0.326161.72
Pentamidine300mgPowderInjection (i.v.)1000.0112340.43−0.53−1.012.442.3164120.17
Pentoxifylline400mgTabletsOral1910.0080278.31−0.160.290.29−2.980.124066.77
Perindopril erbumine8mgTabletsOral8368.48−0.06−0.951.2152101.91
Phenobarbital60mgTabletsOral10.224232.24−2.371.471.34−2.621.373283.96
Phenylbutazone100mgTabletsOral0.70.61308.38−2.643.160.73−3.673.392041.56
Phenylephrine hydrochloride1mg/mLSolution (with promethazine HCl)Injection (i.v.)167.21−0.31−1.890.51−0.092060.00
Pimozide2mgTabletsOral0.0081.0461.56−4.766.304.09−5.026.402133.99
Pramlintide acetate0.6mg/mLSolutionInjection (s.c.)3950.46−17.8360561855.80
Prazosin5mgTabletsOral1.40.010.5383.41−2.440.79−3.622.037196.10
Prednisolone5mgTabletsOral0.380.0516360.45−2.981.621.62−3.681.4253104.22
Primaquine15mgTabletsOral1259.35−0.070.322.604261.59
Prochlorperazine10mgTabletsOral0.10.40.1373.95−3.574.882.98−4.054.38302.92
Proguanil100mgTabletsOral9.090.04253.74−1.452.530.282.535589.44
Promazine100mgTabletsOral333.330.0012284.430.074.552.52−2.044.40201.75
Promethazine50mgTabletsOral2284.434.812.64−2.214.40201.75
Propantheline bromide15mgTabletsOral500.0013.5368.50−0.87−1.07−1.07−4.171.491036.48
Propranolol hydrochloride80mgTabletsOral500.0060.25259.35−0.713.481.20−1.112.753246.24
Propylthiouracil50mgTabletsOral1.20.2170.23−2.151.09−1.830.971246.21
Protriptyline10mgTabletsOral500.00081263.39−0.721.36−1.104.871114.57
Pyrazinamide500mgTabletsOral150.11.6123.12−0.91−0.60−0.59−0.57−0.683166.73
Quetiapine fumarate300mgTabletsOral940.010.5383.52−0.97−3.692.995143.01
Quinacrine; mepacrine100mgTabletsOral28.570.01399.97−1.151.91−2.096.724134.79
Quinidine sulfate dihydrate300mgTabletsOral11.10.118324.43−1.853.441.82−2.672.794143.08
Quinine bisulfate heptahydrate260mgCapsulesOral111.10.00912324.43−0.693.441.82−2.852.794143.08
Rabeprazole sodium20mgCapsulesOral0359.45−3.732.085170.73
Ramelteon8mgTabletsOral0.1259.35−3.492.492141.95
Ramipril10mgCapsulesOral1.5416.521.76−1.271.5452101.91
Reboxetine6mgTabletsOral80.00310313.40−1.59−2.113.264141.58
Remifentanil hydrochloride1mg/mLSolutionInjection (i.v.)0.1376.461.851.25−3.151.964074.45
Reserpine0.25mgTabletsOral0.010.11608.69−4.783.724.14−5.803.8681114.49
Ribavirin200mgTabletsOral1420.00617244.21−0.24−1.85−2.43−0.90−2.8574146.67
Ridogrel5mgTabletsOral0.021.0366.34−4.26−3.584.545172.68
Riluzole50mgTabletsOral2234.20−2.723.243147.02
Rimantadine hydrochloride100mgTabletsOral500.00820179.31−0.550.081.853.961127.97
Risperidone4mgTabletsOral0.250.063410.50−3.223.042.52−3.492.714053.60
Rivastigmine6mgCapsulesOral0.1250.34−1.562.102029.73
Rizatriptan10mgTabletsOral420.001014269.35−0.81−1.190.993139.11
Ropinirole5mgTabletsOral1330.00025260.38−0.292.70−0.332.802133.72
Ropivacaine10mg/mLSolutionInjection (epidural)53.81274.41−0.712.901.15−3.253.162133.72
Rosiglitazone maleate8mgTabletsOral0.040.80357.43−3.95−3.803.025171.34
Rotigotine18mgTransdermalTopical (skin. membranes)5.60.010315.48−1.754.033.40−2.444.542124.05
Roxatidine acetate HCl150mgTabletsOral2384.90−0.55−2.622.804170.19
Salicylic acid300mgTabletsOral2.510.515138.12−1.742.26−1.510.202.193263.70
Scopolamine10mgTabletsOral666.670.000066303.360.340.980.62−1.720.294159.59
Secobarbital (quinalbarbitone)100mgTabletsOral1.10.4238.29−2.341.971.97−2.942.163283.96
Selegiline; (−)-deprenil5mgTabletsOral0.1187.292.902.67−2.323.02101.18
Sertraline hydrochloride100mgTabletsOral3.80.10.2306.24−1.912.74−2.995.351114.57
Sibutramine15mgCapsulesOral2.90.020279.86−1.981.49−2.195.59101.18
Sildenafil100mgTabletsOral3.50.17.5474.59−2.13−4.171.9871105.18
Solifenacin succinate10mgTabletsOral12.5362.48−3.164.682029.42
Sparfloxacin200mgTabletsOral1.10.710392.41−2.55−0.67−0.6173102.79
Sufentanil0.05mg/mLSolutionInjection (i.v.)6386.563.953.24−3.233.593029.11
Sumatriptan succinate100mgTabletsOral21.40.0222295.41−1.140.93−1.17−0.960.743267.24
Sunitinib malate50mgCapsulesOral250.0084398.48−1.205.40−2.583.003380.53
Tacrine40mgCapsulesOral0.5198.272.710.46−0.123.272137.91
Tamoxifen20mgTabletsOral0.50.20.5371.53−2.876.56−4.426.822010.28
Tamsulosin0.4mgCapsulesOral8.7408.52−2.962.1762107.38
Temazepam30mgCapsulesOral0.6040.20.5300.75−2.702.191.79−3.582.343151.32
Temocapril4mgTabletsOral1.5476.62−1.982.1052101.91
Temsirolimus10mg/mLSolutionInjection (i.v.)0.014.61030.31−5.01−9.520.67144253.80
Tenoxicam20mgTabletsOral0.8030.100.1337.38−2.62−0.32−0.171.6152104.05
Terazosin10mgTabletsOral24.20.00210387.44−1.20−4.64−3.712.188195.48
Theophylline600mgTabletsOral8.30.318180.17−1.34−0.04−0.02−1.87−0.033161.90
Thioguanine40mgTabletsOral0.20.80.5167.19−2.92−0.79−1.703376.09
Thiopental1000mgPowderInjection (i.v.)500.080.5242.34−0.692.852.84−3.262.982265.69
Thioridazine200mgTabletsOral10.8370.58−2.575.903.55−3.536.00201.75
Ticlopidine250mgTabletsOral0.5263.793.37−3.484.39101.18
Tilidine; tilidate50mgCapsulesOral0.1273.38−2.773.762028.24
Timolol20mgTabletsOral2.740.0315316.43−2.061.831.91−0.741.217275.98
Tinidazole500mgTabletsOral200.122.5247.27−1.09−0.35−0.33−1.71−0.325091.72
Tolterodine2mgTabletsOral120.00071325.50−1.43−2.285.242124.05
Toremifene60mgTabletsOral0.380.60.1405.97−3.03−4.756.532010.28
Tramadol50mgTabletsOral20263.382.63−0.593.103132.84
Tranylcypromine sulfate10mgTabletsOral480.0008133.19−0.440.69−0.331.481127.97
Triamcinolone4mgTabletsOral0.080.21394.44−3.691.161.16−3.070.7164126.78
Triamcinolone acetonide4mgTabletsOral0.1140.11434.51−3.582.532.30−4.172.216299.25
Triazolam0.5mgTabletsOral0.0450.042343.22−3.882.421.63−4.212.623033.27
Trifluoperazine10mgTabletsOral500.0008407.50−0.915.033.14−3.804.69302.92
Trihexyphenidyl (benzhexol)5mgTabletsOral100.002301.48−1.484.82−1.945.152123.73
Trimetrexate glucuronate200mgPowderInjection (i.v.)500.0220369.43−0.871.63−3.541.8483117.41
Tropisetron5mgCapsulesOral110.0028284.36−1.410.65−1.942.882142.21
Urapidil5mg/mLSolutionInjection (i.v.)1915387.49−1.311.602.02−3.742.446163.11
Valacyclovir1000mgCapletsOral1740.020.5324.34−0.27−1.59−1.2273144.80
Valganciclovir; valcyte450mgTabletsOral700.03354.37−0.70−2.05−1.54−2.1894167.36
Valproic acid250mgTabletsOral1.30.81.8144.22−2.052.750.13−1.452.762140.83
Vardenafil20mgTabletsOral0.110.74488.61−3.65−4.032.2371104.88
Vasopressin60.8μg/mLSolution (20 units per mL)Injection (s.c.)0.151084.25−4.04−2.25−3.821615504.48
Venlafaxine hydrochloride150mgTabletsOral5720.0014.6277.410.31−1.523.273132.84
Verapamil hydrochloride120mgTabletsOral0.750.641.5454.61−3.053.79−4.114.476056.29
Vinblastine1mg/mLSolutionInjection (i.v.)100.5811.00−1.913.703.69−6.975.2393152.61
Vincristine1mg/mLSolutionInjection (i.v.)1015824.98−1.922.57−6.354.0493170.88
Vinorelbine tartrate10mg/mLSolutionInjection (i.v.)100011778.950.11−6.715.9482130.05
Vitamin B6 (pyridoxine)25mgCapsulesOral2220.0005169.180.12−0.77−0.75−0.354378.23
Vitamin D3 (cholecalciferol)1.4mgTabletsOral0.10.06384.65−3.59−6.719.481122.56
Vorozole2.5mgTabletsOral8324.78−4.162.204050.83
Zidovudine300mgCapsulesOral250.052.8267.25−1.030.050.08−2.310.0462127.30
Zolmitriptan5mgTabletsOral200.0018287.36−1.16−1.031.292256.78
Zolpidem tartrate10mgTabletsOral230.0020.5307.40−1.132.35−4.203.033029.96
Zonisamide100mgCapsulesOral0.80.522212.23−2.42−0.10−1.30−0.363188.84
Zopiclone7.5mgTabletsOral0.120.34.5388.82−3.511.50−0.90−2.841.256079.29

Table II

Measured and In Silico Data for 265 BDDCS Class 2 Drugs

Generic nameMaximum strength dose valueMaximum strength dose unitFormulationRouteMeasured solubility (mg/mL)Dose number% Excreted unchanged in urineMW drugMeasured LogS molarMeasured LogPMeasured LogD74minVSLgS 3–7.5CLogPHBAHBDPSA
10-Hydroxy-carbamazepineActive metabolite0.04527254.29−3.751.26−3.151.212232.78
6-Methoxy-2-naphthyl-acetic acidActive metabolite1216.24−0.30−2.292.513149.94
Acitretin25mgCapsulesOral0326.446.40−5.076.073149.94
Adapalene6mgCream, gel, solutionTopical (skin. membranes)412.537.88−5.789.153149.94
Albendazole200mgTabletsOral0265.342.85−3.543.463265.55
Albendazole sulfoxideActive metabolite1281.34−3.283.463265.55
Allopurinol300mgTabletsOral0.5692.112136.11−2.38−0.55−0.55−1.180.633270.47
Altretamine50mgCapsulesOral0.5210.282.73−3.021.676033.35
Aminoglutethimide250mgTabletsOral232.281.41−2.350.773278.79
Amiodarone hydrochloride400mgTabletsOral0.72.30645.32−2.967.802.54−5.408.953037.97
Amphotericin B2mg/mLSolutionInjection (i.v.)0.13.5924.10−3.97−6.40−3.651712347.83
Amprenavir50mgCapsulesOral0.045.01505.64−4.10−5.033.2963139.36
Anidulafungin3.33mg/mLSolutionInjection (i.v.)0.050.51140.27−4.36−10.682.201714415.56
Aprepitant125mgCapsulesOral0534.44−5.284.605278.12
Argatroban1mg/mLSolutionInjection (i.v.)16508.64−1.80−0.5796192.20
Aripiprazole30mgTabletsOral0.000112000.5448.40−6.653.20−4.645.314143.70
Armodafinil250mgTabletsOral8273.36−2.820.942164.62
Artemether50mgTabletsOral298.38−3.353.055049.50
Astemizole10mgTabletsOral0.5458.585.703.88−5.406.094135.37
Atazanavir sulfate300mgCapsulesOral7704.87−7.385.9275186.22
Atorvastatin calcium80mgTabletsOral0.0000204156861558.66−7.44−6.474.4654119.06
Azelastine hydrochloride457μg/mLSolutionOphthalmic2381.911.96−2.374.013033.17
Bevantolol200mgTabletsOral0.18434.38345.44−3.273.003.00−3.153.005264.45
Bexarotene75mgCapsulesOral0.01348.49−4.748.192140.83
Bezafibrate200mgCapsulesOral40361.83−0.17−3.793.704282.78
Bicalutamide50mgTabletsOral0.00540430.38−4.93−4.322.7152110.56
Bosentan125mgTabletsOral0.0015002551.63−5.74−5.384.1792142.96
Buspirone10mgTabletsOral0.02141.90.1385.51−4.262.633.39−3.502.196060.25
Cabergoline0.5mgTabletsOral3451.62−4.284.7742118.24
Calcipotriene; calcipotriol0.05μg/mLSolutionTopical (skin, membranes)0.5412.62−5.585.273367.68
Calcitriol0.5μgCapsulesOral8416.65−6.356.043367.68
Capsaicin179mgCreamTopical0.06120305.42−3.71−4.494.003264.82
Carbamazepine300mgTabletsOral0.2564.70.5236.28−2.972.452.45−3.322.381146.81
Carbamazepine 10,11-epoxideActive metabolite0.10.5252.28−3.400.690.69−3.000.241155.61
Carvedilol25mgTabletsOral0.01101406.49−4.614.19−4.304.045378.42
Cefditoren pivoxil200mgTabletsOral0.08105620.73−3.89−6.882.7192176.19
Cefpodoxime proxetil200mgTabletsOral0.32.70557.61−3.27−4.790.80102183.53
Celecoxib200mgCapsulesOral0.0051602381.38−4.88−4.474.373178.91
Chlorzoxazone500mgTabletsOral0.258.00.5169.57−2.83−1.772.512142.53
Ciclesonide0.16mg/inhalationSolutionTopical (nasal)0.00023.20540.70−6.43−6.255.2561103.75
Cilostazol100mgTabletsOral0.003133369.47−5.09−4.873.535181.66
Cinacalcet90mgTabletsOral0.13.60.1357.42−3.55−3.126.351114.57
Cisapride20mgTabletsOral0.002730465.96−5.243.39−4.573.816288.69
Citalopram40mgTabletsOral0.0315.212324.40−4.023.410.74−2.833.133028.67
Cladribine1mg/mLSolutionInjection (i.v.)18285.690.020.24−2.15−0.9173112.88
Clofazimine50mgCapsulesOral0.0012000.2473.41−5.687.48−5.847.704134.09
Clofibrate500mgCapsulesOral11242.703.603.60−1.633.023136.17
Clopidogrel bisulfate75mgTabletsOral0.050785.9321.83−3.80−3.834.212028.24
Clotrimazole10mgTabletsOral0.003135344.85−5.064.80−5.075.251010.81
Clozapine100mgTabletsOral0.0118340.5326.83−4.443.232.99−4.373.714125.63
Conivaptan hydrochloride5mg/mlSolutionInjection (i.v.)0.151498.59−3.55−6.735.003275.90
Cyclosporine100mgCapsulesOral0.008500.11202.64−5.182.952.92−10.7314.36125290.07
Cyproterone acetate50mgTabletsOral0.0021951416.95−5.30−4.833.963063.61
Danazol200mgCapsulesOral0.0009889337.47−5.57−4.543.932145.90
Dapsone100mgTabletsOral0.22.015248.31−3.090.970.97−2.710.894292.10
Darunavir600mgCapsulesOral0.15161.2547.68−3.56−5.442.8973148.15
Dasatinib70mgTabletsOral0.1488.02−4.702.8883101.85
Daunorubicin5mg/mLSolutionInjection (i.v.)0.03920.5527.53−4.131.831.83−3.890.84115200.34
Delavirdine200mgCapletsOral0.000819882.5456.57−5.75−4.802.4163110.60
Desloratadine5mgTabletsOral0.0000772605310.83−6.61−2.423.832124.82
Diazoxide100mgCapsulesOral0.152.735230.67−3.191.811.08−2.001.423161.41
Dicoumarol100mgTabletsOral0.1283.10.5336.30−3.422.071.86−3.063.6642101.12
Diflunisal500mgTabletsOral6250.204.440.76−2.174.403263.70
Diloxanide furoate500mgTabletsOral1328.151.96−4.033.092055.94
Dipyridamole75mgTabletsOral0.007430.1504.64−4.863.71−4.211.49124134.70
Disulfiram250mgTabletsOral0.25.00296.54−3.173.883.88−4.193.88002.35
Docetaxel40mg/mLSolutionInjection (i.v.)0.00655807.90−5.09−7.054.08105240.13
Domperidone20mgTabletsOral0.006130425.92−4.853.903.33−4.314.273266.80
Donepezil10mgTabletsOral0.00291410.6379.50−5.12−4.104.604037.66
Dronabinol; tetrahydrocannabinol10mgCapsulesOral0.5314.476.973.78−5.917.242131.98
Dronedarone400mgTabletsOral0.53.20556.77−3.05−4.248.575189.77
Drospirenone3mgTabletsOral0.1366.50−4.112.842045.34
Dutasteride0.5mgCapsulesOral0.5528.54−6.054.942265.39
Ebastine10mgTabletsOral2469.672.78−5.876.943028.24
Efavirenz600mgCapsulesOral0.0054800.5315.68−4.80−3.994.672141.34
Entacapone200mgTabletsOral0.0166480.2305.29−4.26−2.731.7662128.04
Eplerenone50mgTabletsOral3414.500.85−4.020.294081.19
Erlotinib hydrochloride163.9mgTabletsOral0.41.60.3393.45−2.99−5.204.347170.25
Estazolam2mgTabletsOral0.00155.34294.75−5.29−3.732.293033.27
Ethchlorvynol750mgCapsulesOral0.05144.602.06−2.161.571122.56
Etizolam1mgTabletsOral0.3342.85−3.822.873033.27
Etodolac600mgTabletsOral0.012401287.36−4.463.811.14−2.813.433263.59
Etomidate2mg/mLSolutionInjection (i.v.)0.0452244.30−3.733.053.05−3.492.672037.88
Etoricoxib; arcoxia120mgTabletsOral0.143.40.5358.85−3.41−4.522.354057.25
Etravirine100mgTabletsOral0435.29−6.765.2262108.94
Exemestane25mgTabletsOral1296.41−3.953.282036.54
Ezetimibe10mgTabletsOral2409.44−5.563.963264.57
Febuxostat80mgTabletsOral0.013253316.38−4.39−3.594.405178.88
Felodipine10mgTabletsOral0.001400.25384.26−5.583.86−4.735.303168.70
Fenofibrate145mgCapsulesOral0.00087250.1360.84−5.654.80−5.475.233054.44
Flufenamic acid100mgTabletsOral0.0265157281.24−4.035.252.06−3.415.533254.80
Flunarizine10mgTabletsOral0.01652.40.2404.51−4.395.784.90−5.696.34202.35
Fluphenazine hydrochloride10mgTabletsOral0.0311.30.1437.53−4.223.48−4.114.124125.48
Flurbiprofen100mgCapsulesOral2.9244.274.160.91−2.763.752140.83
Flutamide125mgCapsulesOral0.0095530.5276.22−4.463.354.06−3.173.343176.69
Fluticasone propionate50μg/inhalationSuspensionTopical (nasal)0.000513.93500.58−5.99−4.823.804186.17
Folic acid5mgTabletsOral0.001613441.41−5.44−0.52−2.59−2.31126219.42
Fosamprenavir calcium700mgCapsulesOral0.319.00585.62−3.28−0.533.0484189.86
Fosinopril40mgTabletsOral0.0227.30563.68−4.412.32−5.957.4551115.00
Fulvestrant50mg/mLSolutionInjection (i.m.)0.0012000.1606.79−5.78−8.287.353263.81
Gefitinib250mgTabletsOral0.00175882446.91−5.424.85−4.775.607162.63
Gemfibrozil600mgTabletsOral0.0191260.5250.34−4.121.33−3.153.943149.94
Gliclazide80mgTabletsOral0.0039820.5323.42−4.921.36−0.07−2.981.094289.39
Glimepiride4mgTabletsOral0.0012130490.63−5.61−5.703.9653137.24
Glipizide10mgTabletsOral4.5445.541.91−0.40−4.492.5763138.28
Glyburide; glibenclamide6mgTabletsOral0.0046.00494.01−5.091.41−5.474.2453126.89
Griseofulvin500mgTabletsOral0.3352.772.182.18−3.191.916072.65
Haloperidol20mgTabletsOral0.0372.21375.87−4.014.303.16−3.683.853142.01
Ibuprofen800mgCapsulesOral0.038840.5206.29−3.733.970.81−2.313.682140.83
Idebenone180mgCapsulesOral0.5338.45−4.813.425176.69
Iloperidone12mgTabletsOral0.031.60.5426.49−4.15−3.874.275061.00
Imatinib mesylate400mgCapsulesOral11.65493.62−2.69−5.774.537279.59
Indinavir sulfate400mgCapsulesOral0.015107613.81−4.612.92−6.213.6874123.40
Indobufen200mgTabletsOral13295.34−0.70−3.203.273159.98
Indomethacin50mgTabletsOral0.00258015357.80−5.164.270.77−3.934.184168.78
Indoramin25mgTabletsOral5347.463.232.29−3.862.842247.99
Irbesartan300mgTabletsOral0.08152.5428.54−3.731.00−2.826.045182.47
Isotretinoin; 13-cis-retinoic acid40mgCapsulesOral0.5300.446.304.23−4.806.742140.83
Isradipine5mgCapsulesOral0.0082.50371.40−4.674.283.67−4.143.9251105.96
Itraconazole100mgCapsulesOral0.0000014000000.03705.65−8.855.663.27−8.445.999084.66
Ixabepilone1.915mg/mLSolutionInjection (i.v.)5.6506.71−5.513.0863115.27
Ketanserin40mgTabletsOral0.053.20.5395.44−3.903.292.18−5.103.004170.53
Ketoconazole200mgTabletsOral0.00691163531.44−4.894.354.05−5.993.646057.83
Ketoprofen75mgCapsulesOral0.181.70.5254.29−3.153.12−0.01−2.822.763159.10
Lamotrigine200mgTabletsOral0.174.710256.10−3.18−0.19−2.752.535288.97
Lansoprazole30mgCapsulesOral0.000971240369.37−5.582.36−3.742.604161.94
Lapatinib ditosylate250mgTabletsOral0.00110001581.07−5.76−7.195.9772104.31
Latanoprost0.5mg/mLSolutionOphthalmic0.05432.61−3.94−6.143.604394.74
Leflunomide100mgTabletsOral0.023171270.21−4.07−2.992.322155.88
Lofepramine70mgTabletsOral4418.976.57−6.587.293020.02
Lopinavir200mgCapsules (with 50 mg ritonavir)Oral2.2628.82−7.326.1054131.37
Loratadine10mgTabletsOral0.0058.05382.89−4.885.205.20−5.325.052038.48
Losartan potassium100mgTabletsOral0.0488.312422.92−3.98−2.044.105286.79
Lovastatin40mgTabletsOral0.000440010404.55−6.004.264.26−4.954.083176.69
Mebendazole100mgTabletsOral295.302.832.42−4.003.084283.82
Mefenamic acid250mgTabletsOral0.08131241.29−3.485.12−3.365.293254.80
Mefloquine250mgTabletsOral9378.320.72−3.123.673247.38
Meloxicam15mgTabletsOral0.0125.00.2351.41−4.473.020.10−2.152.2952104.05
Mercaptopurine; 6-mercaptopurine50mgTabletsOral22152.180.010.391.740.823244.70
Mesalamine; mesalazine1200mgTabletsOral14.87153.14−2.19−3.201.971.064391.37
Metaxalone800mgTabletsOral0.3112221.26−2.872.42−2.492.152150.74
Methaqualone500mgTabletsOral0.36.70.2250.30−2.922.502.50−3.833.652028.78
Miconazole1200mgCream, suppositoryTopical (skin, membranes)0.895.40416.14−2.675.346.34−5.835.812019.61
Mizolastine10mgTabletsOral0.0133.15432.50−4.52−5.282.845155.05
Modafinil200mgTabletsOral8273.36−2.920.942164.62
Mometasone furoate200μg/activationPowderTopical (aerosol)0.5521.44−5.874.124189.90
Montelukast sodium10mgTabletsOral0.2586.20−7.758.474273.63
MycophenolateActive metabolite0.5320.350.20−3.442.295299.87
Mycophenolate mofetil500mgTabletsOral0.043470433.51−4.002.37−4.672.986196.07
Nabumetone750mgTabletsOral0.0152000228.29−4.183.083.38−3.512.982027.38
Nalidixic acid1000mgTabletsOral0.05474232.24−3.631.590.59−1.881.025169.92
Naproxen500mgTabletsOral0.115170.5230.27−3.303.181.70−2.502.823149.94
Nateglinide120mgTabletsOral0.3221.513317.43−2.99−3.534.303273.68
Nefazodone100mgTabletsOral0.1470.025.00−5.945.735043.72
Nelarabine5mg/mLSolutionInjection (i.v.)16.6297.27−2.47−1.56−0.4694112.88
Nelfinavir625mgTabletsOral567.80−6.895.8454112.29
Nevirapine200mgTabletsOral0.18.0266.31−3.431.81−3.152.654153.60
Nifedipine20mgCapsulesOral0.006130.01346.34−4.762.202.80−3.663.1351112.85
Nifurtimox250mgTabletsOral1287.30−2.020.0260104.39
Nilotinib200mgCapsulesOral4529.53−1.10−7.565.846287.75
Nilvadipine2mgTabletsOral0.00136.20385.38−5.47−4.103.0461131.55
Nimesulide100mgTabletsOral0.014292308.31−4.341.79−3.013.2141105.36
Nimodipine30mgCapsulesOral0.0025480.5418.45−5.223.052.86−4.684.0061121.64
Nitrazepam10mgCapsulesOral0.02541.60.5281.27−4.042.252.16−3.512.324186.30
Nitrendipine20mgCapsulesOral0.0022360.5360.37−5.212.88−4.203.7351112.85
Norelgestromin6mgTabletsOral327.472.70−4.564.103257.94
Norethindrone acetate5mgTabletsOral0.0054.00340.47−4.83−4.893.932145.34
Olanzapine40mgTabletsOral0.01167312.44−4.493.00−3.793.014125.63
Oxaprozin600mgTabletsOral1.71.40.5293.33−2.244.191.03−3.582.953160.49
Oxatomide30mgTabletsOral0.0432.80426.57−4.005.423.39−5.495.623135.16
Oxazepam30mgTabletsOral0.0452.70.5286.72−3.802.242.24−3.552.313264.71
Oxcarbazepine600mgTabletsOral0.08528252.28−3.471.25−3.181.212165.09
Paclitaxel6mg/mLSolutionInjection (i.v.)5853.936.83−7.354.73104235.84
Paricalcitol4μgCapsulesOral0416.65−6.295.693367.68
Pentazocine50mgTabletsOral0.04494.515285.43−3.803.310.83−2.064.672124.05
Pergolide1mgTabletsOral314.503.97−3.984.401115.14
Perhexiline100mgTabletsOral0.000066667277.50−6.673.93−1.417.151114.57
Phenacetin500mgTabletsOral0.732.7179.22−2.391.58−2.161.772141.65
Phenytoin sodium300mgTabletsOral0.02602252.28−4.142.472.47−3.252.092265.69
Pimecrolimus10mg/gCreamTopical (skin, membranes)0810.47−8.005.30102163.34
Pioglitazone45mgTabletsOral0.5356.45−1.083.534170.46
Piroxicam20mgCapsulesOral0.0073115331.35−4.663.060.20−0.231.8952104.05
Pitavastatin4mgTabletsOral421.471.50−1.513.595396.19
Posaconazole40mg/mLSuspensionOral0.000050.1700.80−7.15−7.924.119198.43
Prasugrel10mgTabletsOral1373.45−4.263.433046.82
Prazepam30mgTabletsOral0.004300324.81−4.913.733.73−4.533.932028.76
Praziquantel600mgTabletsOral0.46.02312.42−2.892.44−3.893.362038.89
Prednisone50mgTabletsOral0.1331.53358.44−3.431.461.46−3.571.665299.93
Primidone250mgTabletsOral0.61.735218.26−2.560.91−0.84−2.590.882265.69
Probenecid500mgTabletsOral1.2285.363.21−0.26−2.363.374179.53
Probucol500mgTabletsOral516.8610.40−8.3210.972245.74
Progesterone200mgCapsulesOral0.0071140314.47−4.653.87−4.253.782036.54
Propafenone hydrochloride300mgTabletsOral0.093130.5341.45−3.56−2.213.644264.51
Propofol10mg/mLEmulsionInjection (i.v.)0.1640.5178.28−3.043.794.16−3.293.931122.87
Propoxyphene napsylate500mgTabletsOral0.0196102367.54−4.27−0.955.322141.64
Proscillaridin0.5mgCapsulesOral530.662.482.48−5.093.6674135.51
Pyrantel pamoate180mgCapletOral0.51.47206.31−2.621.013.032010.79
Quazepam15mgTabletsOral386.804.033.87−4.623.201010.48
Quinapril40mgTabletsOral0.0011603.1438.53−5.642.26−1.821.7452101.91
Raloxifene; keoxifene60mgTabletsOral0.013180.1473.60−4.56−5.566.865274.29
Raltegravir potassium400mgTabletsOral9444.430.45−3.791.1673150.45
Ranolazine1000mgTabletsOral6427.55−4.581.016275.66
Repaglinide2mgTabletsOral1.5452.60−2.425.305283.65
Rifabutin150mgCapsulesOral0.193.210847.03−3.653.20−5.364.73135216.49
Rifampin300mgCapsulesOral7822.961.32−4.363.71146233.54
Ritonavir100mgCapsulesOral3.5720.96−8.084.9464151.55
Rofecoxib50mgTabletsOral0.12.01314.36−3.50−2.831.803063.82
Romidepsin5mg/mLSolutionInjection (i.v.)540.71−4.163.4454158.44
Rufinamide400mgTabletsOral0.059271238.20−3.61−2.260.513173.11
Salmeterol xinafoate0.05mgPowderTopical (aerosol)2.5415.58−3.013.065491.35
Saquinavir methanesulfonate500mgCapsulesOral0.08252670.86−3.984.70−6.914.7375178.75
Simvastatin80mgTabletsOral0.031110418.58−4.144.684.68−5.154.483176.69
Sirolimus2mgTabletsOral2914.20−9.327.04123204.17
SN-38; 7-ethyl-10-hydroxycamptothecinActive metabolite0.5392.42−4.371.9752101.58
Sorafenib tosylate200mgTabletsOral0464.83−5.955.463399.32
Spironolactone100mgTabletsOral0.022180.5416.58−4.282.262.26−4.582.653063.61
Sulfamethoxazole800mgTabletsOral0.3928.214253.28−2.810.89−2.120.5642102.81
Sulfasalazine500mgTabletsOral0.00248331.5398.40−5.22−0.78−3.463.8883148.16
Sulfinpyrazone200mgCapsulesOral0.0312639404.49−4.122.30−0.08−3.611.663059.94
Sulindac200mgTabletsOral0.00282861356.42−5.103.42−0.66−4.163.163159.21
Sulindac sulfideActive metabolite0.00280.5340.42−5.08−4.383.163140.83
Tacrolimus5mgCapsulesOral0.0082.50.5804.04−5.003.96−7.745.78113185.90
Tadalafil20mgTabletsOral389.41−4.462.584171.07
Tegaserod maleate6mgTabletsOral0.5301.39−3.062.815488.12
Telithromycin400mgTabletsOral0.82.013812.03−3.01−3.703.75111163.02
Telmisartan80mgTabletsOral0.5514.63−4.727.544162.46
Temozolomide250mgCapsulesOral5.6194.15−1.48−0.8151101.89
Teniposide10mg/mLSolutionInjection (i.v.)0.0259656.67−4.421.243.09−5.240.72123166.64
Terbinafine250mgTabletsOral291.446.00−4.715.96101.18
Terfenadine60mgTabletsOral0.006400471.69−4.905.694.77−5.486.073246.29
Testolactone50mgTabletsOral0.0277.4300.40−4.05−3.862.632045.34
Testosterone40mgCapsulesOral0.02346.8288.43−4.093.32−3.923.222140.83
Tetrabenazine25mgTabletsOral0317.43−2.413.814037.66
Thalidomide200mgCapsulesOral0.0525150.5258.24−3.690.33−2.540.534188.83
Thiabendazole500mgTabletsOral0.05400.1201.25−3.602.47−3.012.362134.46
Thyroxine; levothyroxine0.3mgTabletsOral0.0005852.10776.88−6.120.65−3.173.5143101.09
Tiagabine hydrochloride16mgTabletsOral0.032.12375.56−4.10−1.872.783142.01
Tiaprofenic acid300mgTabletsOral2.5260.312.51−0.86−2.422.543159.10
Tibolone2.5mgTabletsOral0312.46−4.683.152140.83
Tipranavir500mgTabletsOral0.1602.68−6.527.7652111.66
Tizanidine6mgCapsulesOral253.71−2.402.095258.53
Tolazamide500mgTabletsOral0.2787.2311.41−3.052.690.09−3.031.344289.39
Tolbutamide200mgTabletsOral0.1097.30270.35−3.392.342.52−2.862.503284.94
Tolcapone200mgTabletsOral0.5273.25−3.113.2552108.16
Tolfenamic acid200mgTabletsOral8261.715.17−3.555.663254.80
Tolmetin600mgTabletsOral0.22117257.29−3.072.79−0.98−2.292.213159.67
Tolvaptan30mgTabletsOral0.00052400448.95−5.95−6.284.653274.25
Torsemide, torasemide100mgTabletsOral0.161.5620348.433.370.45−1.043.3653109.16
Trandolapril4mgTabletsOral430.551.08−1.682.1052101.91
Trazodone300mgTabletsOral0.26.00.5371.87−3.273.802.64−4.923.854034.31
Treprostinil10mg/mLSolutionInjection (s.c.)4390.52−4.333.725395.05
Tretinoin10mgCapsulesOral0.5300.446.304.23−4.716.742140.83
Triamterene100mgCapsulesOral0.0291410253.27−3.940.981.30−2.541.6173123.98
Triclabendazole250mgTabletsOral0.000250002359.66−6.252.31−5.396.441133.63
Trimipramine maleate100mgTabletsOral294.441.98−2.355.44201.75
Ursodiol; ursodeoxycholic acid500mgTabletsOral0.5392.584.152.03−4.684.514385.95
Valdecoxib; bextra20mgTabletsOral314.37−3.931.833188.84
Vitamin A (retinol)110mgTabletsOral0.044100286.46−3.815.68−5.126.401122.56
Vitamin D2 (ergocalciferol)1.25mgCapsulesOral396.667.04−6.639.391122.56
Voriconazole200mgTabletsOral0.392.11.5349.32−2.95−3.200.525167.01
Warfarin10mgTabletsOral0.0182.21308.34−4.232.601.12−3.402.903168.83
Zafirlukast20mgTabletsOral0575.69−6.677.0962121.38
Zaleplon10mgCapsulesOral0.5305.341.23−4.191.445061.50
Zileuton600mgTabletsOral0.54.8236.29−2.67−2.162.482273.18
Ziprasidone hydrochloride80mgCapsulesOral0.000437440.5412.94−5.98−4.924.214144.63

Table III

Measured and In Silico Data for 247 BDDCS Class 3 Drugs

Generic nameMaximum strength dose valueMaximum strength dose unitFormulationRouteMeasured solubility (mg/mL)Dose number% Excreted unchanged in urineMW drugMeasured LogS molarMeasured LogPMeasured LogD74minVSLgS 3–7.5CLogPHBAHBDPSA
Acamprosaic acid333mgTabletsOral50181.210.72−2.474292.63
Acecainide; N-acetyl procainamideActive metabolite5081277.37−0.74−0.911.643266.56
Acrivastine8mgCapsulesOral0.70.0567348.45−2.70−2.111.464152.25
Adefovir dipivoxil10mgTabletsOral0.40.145333.24−2.92−1.63−1.9883149.47
Albuterol; salbutamol4mgTabletsOral50239.32−1.110.450.064482.56
Alendronate sodium70mgTabletsOral45249.104.87−5.6486178.77
Almotriptan12.5mgTabletsOral40335.47−1.461.793153.85
Alvimopan12mgCapsulesOral0.10.52424.54−3.63−1.822.165397.72
Amantadine100mgCapsulesOral500.00885151.25−0.482.44−0.692.002.001127.97
Amikacin250mg/mLSolutionInjection (i.v.)98585.615.31−6.301713360.37
Amiloride5mgTabletsOral500.000449229.63−0.660.10−1.25−1.030.1175159.65
Aminocaproic acid1000mgTabletsOral3330.0165131.180.40−2.95−1.602.05−2.243268.80
Amoxicillin875mgTabletsOral3.51.086365.41−2.020.87−1.52−0.47−1.8764143.96
Ampicillin500mgCapsulesOral7.80.388349.41−1.651.35−1.61−0.42−1.2053121.09
Atenolol100mgTabletsOral24.80.0294266.34−1.030.16−1.03−0.16−0.114392.48
Atropine (DL)0.4mgTabletsOral0.0020.857289.38−5.161.83−0.961.303150.80
Azacitidine25mg/mLSolutionInjection (i.v.)8962244.21−0.44−3.02−0.83−2.2084143.47
Azithromycin600mgTabletsOral390.066749.00−1.284.02−3.152.64135186.17
Azlocillin4000mgPowderInjection (i.v.)500.365461.50−0.97−2.821.5664159.99
Aztreonam40mg/mLSolutionInjection (i.v.)1068435.44−1.64−5.071.070.34114213.20
Baclofen20mgTabletsOral2.10.0469213.67−2.01−0.96−0.960.91−0.623268.80
BenazeprilatActive metabolite18396.45−0.07−0.892.0463115.38
Bendroflumethiazide10mgTabletsOral0.1080.421421.42−3.591.891.99−3.421.7353131.87
Betamipron5mg/mLSolution (with panipenem)Injection (i.v.)98193.20−1.180.723273.68
Biapenem300mgPowderInjection (i.v.)53350.40−0.67−6.355197.13
Biotin5mgTabletsOral0.220.0943244.31−3.05−1.14−0.083388.25
Bisoprolol fumarate10mgTabletsOral63325.451.87−0.23−1.521.835263.82
Bleomycin A23mg/mLSolutionInjection (i.v.)20681415.58−1.85−7.03−7.682820662.79
Bretylium50mg/mLSolutionInjection (i.v.)5077243.17−0.69−2.10−1.93−1.25000.00
Bumetanide2mgTabletsOral0.10.0845364.42−3.56−0.45−3.553.3753130.02
Cadralazine10mgTabletsOral1.30.0375283.33−2.340.32−2.800.9363106.01
Capreomycin 1B500mg/mLSolutionInjection (i.v.)90653.701.99−5.511113389.22
Captopril100mgTabletsOral1600.00338217.29−0.130.34−1.98−1.040.893260.28
Carbenicillin382mgTabletsOral500.0382378.41−0.881.13−1.331.6463133.95
Carboplatin10mg/mLSolutionInjection (i.v.)1477371.26−1.42−2.300.94−0.3422149.65
Carteolol10mgTabletsOral60292.38−0.46−0.761.294378.78
Cefaclor500mgCapsulesOral8.590.252367.81−1.63−1.76−0.17−1.6453121.09
Cefadroxil1000mgTabletsOral14.20.393363.39−1.41−3.400.14−2.5164143.96
Cefamandole400mgTabletsOral3330.00596462.51−0.140.50−2.40−2.540.1183155.70
Cefazolin1000mgPowderInjection (i.v.)330.180454.51−1.14−0.58−3.14−1.36−1.1992156.53
Cefepime2000mgPowderInjection (i.v.)85480.57−0.27−3.0582152.65
Cefmetazole sodium40mg/mLSolutionInjection (i.v.)0.094280471.54−3.70−0.60−2.34−1.3492160.63
Cefodizime50mg/mLSolutionInjection (i.v.)27080584.67−0.34−1.001.10114203.72
Cefonicid20mg/mLSolutionInjection (i.v.)99542.57−1.71−1.92114215.48
Ceforanide50mg/mLSolutionInjection (i.v.)84519.560.00−3.36104201.94
Cefotaxime40mg/mLSolutionInjection (i.v.)30455.47−1.70−0.310.1493179.71
Cefotetan50mg/mLSolutionInjection (i.v.)67575.62−1.20−2.04−1.54114229.00
Cefotiam167mg/mLSolutionInjection (i.v.)80525.63−0.79−3.58103172.22
Cefoxitin50mg/mLSolutionInjection (i.v.)100085427.460.37−0.02−1.89−1.42−0.8163156.95
Cefsulodin500mgPowderInjection (i.v.)500.0460532.55−1.03−1.96−6.8983199.72
Ceftazidime20mg/mLSolutionInjection (i.v.)585546.58−2.04−1.60−3.80−0.46−3.75103194.05
Ceftizoxime40mg/mLSolutionInjection (i.v.)93383.410.410.3483152.65
Ceftriaxone40mg/mLSolutionInjection (i.v.)40046554.59−0.14−4.300.310.02124216.88
Cefuroxime50mgTabletsOral2000.00196424.39−0.33−0.16−1.91−1.760.2373179.19
Celiprolol200mgTabletsOral1510.00520379.50−0.401.921.14−1.731.865398.23
Cephalexin750mgCapsulesOral120.391347.40−1.46−0.67−2.40−0.28−1.8453121.09
Cephalothin sodium2000mgPowderInjection (i.v.)500.252396.44−0.920.00−2.20−1.72−0.2853120.19
Cephapirin1000mgPowderInjection (i.v.)48423.47−1.15−1.15−0.27−0.6162130.43
Cephradine500mgCapsulesOral260.0886349.41−1.13−1.75−2.10−0.07−1.7353121.09
Cetirizine10mgTabletsOral0.1010.450388.90−3.591.70−0.31−1.422.085151.97
Chloroquine500mgTabletsOral1000.0261319.88−0.504.631.54−1.175.063125.69
Cidofovir75mg/mLSolutionInjection (i.v.)17090279.19−0.222.99−2.3984152.23
Cilastatin250mg/mLSolution (with imipenem)Injection (i.v.)2570358.46−1.16−1.100.770.4764142.48
Cilazaprilat2.6mgTabletsOral91389.461.011.5073120.13
Cimetidine800mgTabletsOral6.20.562252.34−1.610.400.33−1.910.195381.67
Clarithromycin500mgTabletsOral21.035747.97−2.573.16−4.002.37134189.50
Clavulanic acid125mgTablets (with 875 mg amoxicillin)Oral43199.160.31−1.075291.63
Clofarabine1mg/mLSolutionInjection (i.v.)155303.68−2.48−1.97−0.4673112.88
Clonidine0.3mgTabletsOral62230.101.430.83−1.461.733238.46
Cromolyn5.2mg/inhalationSolutionTopical (nasal)2100.000150468.38−0.351.92−4.80−2.331.48113177.81
Cycloserine250mgCapsulesOral1000.0165102.09−0.011.25−1.193272.82
DabigatranActive metabolite85471.52−2.280.0684146.28
Dacarbazine10mg/mLSolutionInjection (i.v.)4.239182.19−1.64−0.24−0.24−1.560.485297.62
Dactinomycin; actinomycin D0.5mg/mLSolutionInjection (i.v.)0.5101255.45−3.40−6.898.01185368.53
Dalfampridine10mgTabletsOral90.394.120.261.510.322137.91
Daptomycin50mg/mLSolutionInjection (i.v.)100040.51620.71−0.21−7.54−2.432722774.05
Demeclocycline300mgTabletsOral1.50.847464.86−2.49−0.600.39−0.5996197.07
Desmopressin0.2mgTabletsOral471069.24−2.48−3.141514476.51
Desvenlafaxine100mgTabletsOral5720.000745263.380.340.21−1.282.683234.13
Dexrazoxane500mgPowderInjection (i.v.)110.242268.27−1.39−1.60−2.12−1.3362104.58
Dibekacin; dideoxykanamycin B50mg/mLAmpoulesInjection (i.m.)81451.521.70−3.41139265.26
Dicloxacillin500mgCapsulesOral60470.332.91−3.362.9852116.46
Didanosine25mgTabletsOral27.30.00455236.23−0.94−1.24−1.24−1.62−1.656284.65
Digitoxin0.1mgTabletsOral0.010.0430764.96−4.882.832.83−6.012.85125192.62
Digoxin0.25mgTabletsOral0.9860.00160780.96−2.901.261.26−6.301.42136215.17
Disopyramide150mgCapsulesOral10.655339.48−2.532.58−0.43−0.792.583157.66
Dofetilide0.5mgCapsulesOral64441.57−3.351.9962113.88
Dorzolamide hydrochloride0.02mg/mLSolutionOphthalmic3.910324.44−1.921.31−0.4352116.83
Doxycycline40mgTabletsOral41444.45−0.02−0.060.52−0.5196197.07
Edetate calcium disodium200mg/mLSolutionInjection (i.v.)9195292.25−0.516.61−1.93104165.67
Emtricitabine200mgCapsulesOral1120.00773247.25−0.34−0.43−0.43−1.31−1.295288.11
Enalaprilat8mgTabletsOral60348.40−0.74−0.280.210.8863115.68
Entecavir1mgTabletsOral2.40.00270277.29−2.06−2.13−2.5864126.09
Eptifibatide2mg/mLSolutionInjection (i.v.)6550831.98−1.11−5.02−2.861211350.27
Ertapenem sodium1000mgPowderInjection (i.v.)38475.52−0.26−1.8285170.78
Erythromycin (base)500mgTabletsOral2.11.05733.95−2.543.06−3.841.61135203.27
Erythromycin lactobionate50mg/mLSolutionInjection (i.v.)2051074.21−1.73−3.841.61135203.27
Ethambutol400mgTabletsOral79204.31−2.791.550.124474.26
Etidronic acid400mgTabletsOral50206.03−8.864.72−2.5475150.80
Etoposide50mgCapsulesOral0.220.938588.57−3.430.600.60−4.310.03123166.64
EXP-3174Active metabolite55436.90−1.505.5962105.06
Famotidine40mgTabletsOral67337.45−0.64−1.50−1.64−1.1786179.34
Ferrous sulfate182mgCapsulesOral5700.001151.910.573.65−4.154075.52
Fexofenadine; terfenadine carboxylate180mgTabletsOral25501.672.68−3.081.965387.12
Flecainide150mgTabletsOral48.40.0143414.35−0.933.781.14−2.203.664265.63
Fluconazole200mgCapsulesOral10.875306.28−2.490.500.95−2.35−0.445170.48
Flucytosine500mgCapsulesOral150.199129.09−0.93−1.970.05−1.643270.15
Foscarnet24mg/mLSolutionInjection (i.v.)82126.01−2.003.43−2.1753104.95
Fosfomycin tromethamine3000mgTabletsOral500.282138.06−0.444.57−0.234272.91
Gabapentin800mgTabletsOral100.3100171.24−1.23−1.10−1.311.75−0.663268.80
Gallium nitrate25mg/mLSolutionInjection (i.v.)80255.731.711.4390199.71
Ganciclovir sodium500mgCapsulesOral60.391255.24−1.66−1.66−4.25−1.52−2.7384134.88
Gentamicin C1 sulfate40mg/mLSolutionInjection (i.v.)5091477.61−0.98−8.403.49−1.80128215.91
Gold sodium thiomalate50mg/mLSolutionInjection (i.m.)70368.091.90−3.304181.66
Guanfacine hydrochloride2mgTabletsOral10.00850246.10−2.391.331.12−2.161.373383.82
Hydrochlorothiazide50mgTabletsOral0.60.3100297.74−2.70−0.07−0.07−1.75−0.3753131.87
HydrodolasetronActive metabolite53326.40−1.441.903264.77
Hydroflumethiazide50mgTabletsOral0.30.790331.29−3.040.360.36−1.88−0.2153131.87
Hydroxyurea1000mgTabletsOral500.088076.06−0.18−1.801.19−1.802386.58
Hyoscyamine; l-atropine311μgTabletsOral3.560.000357289.38−1.911.83−0.44−0.881.303150.80
Ibandronate150mgTabletsOral55319.232.10−3.3785151.98
ImidaprilatActive metabolite9377.400.461.7473137.49
Imipenem750mgPowderInjection (i.v.)100.369299.35−1.480.82−1.3564120.42
Iohexol755mg/mLSolution (equivalent to 350 mg I per mL)Injection (i.v.)95821.15−4.120.6698220.19
Iopamidol755mg/mLSolution (equivalent to 370 mg I per mL)Injection (i.v.)96777.09−3.880.8688211.03
Iopromide769mg/mLSolution (equivalent to 370 mg I per mL)Injection (i.v.)97791.12−3.901.3786183.86
Ipratropium bromide17μg/activationSolutionTopical (aerosol)50332.47−2.28−2.192149.62
Kanamycin333mg/mLSolutionInjection (i.v.)90484.513.84−5.171511304.97
Ketorolac10mgTabletsOral2000.000258255.28−0.111.04−2.371.623159.67
Lacosamide; erlosamide50mgTabletsOral20.140250.30−2.10−2.150.393274.48
Lamivudine300mgTabletsOral700.0267229.26−0.52−0.93−1.21−1.465288.11
Latamoxef; moxalactam100mg/mLSolutionInjection (i.v.)5076520.48−1.02−0.58−3.45−1.98−0.82124214.42
Leucovorin; folinic acid25mgTabletsOral5000.000210473.450.02−7.85−1.81−3.49127232.35
Levalbuterol45μg/activationSolutionTopical (aerosol)1800.00000146239.32−0.12−1.110.450.064482.56
Levetiracetam1000mgTabletsOral10400.00466170.210.79−1.18−0.342165.69
Levocetirizine5mgTabletsOral0.1010.271388.90−3.591.70−0.31−1.542.085151.97
Levofloxacin750mgTabletsOral500.0674361.38−0.86−0.39−0.40−0.45−0.517170.83
Lincomycin300mg/mLSolutionInjection (i.v.)5030406.55−0.910.56−2.271.2875133.05
Lisinopril40mgTabletsOral970.00294405.50−0.62−1.22−3.401.85−1.6974143.65
Lithium carbonate600mgTabletsOral130.29573.89−0.750.00−3.653063.19
Lomefloxacin400mgTabletsOral1.641.065351.36−2.33−0.30−1.03−0.56−0.116275.12
Loperamide2mgCapsulesOral1.40.0060.5477.05−2.534.22−4.574.663143.18
Loracarbef400mgCapsulesOral410.0494349.78−0.93−0.36−0.4753121.09
Memantine10mgTabletsOral71179.313.281.353.031127.97
Metformin1000mgTabletsOral99129.17−5.414.13−1.635489.74
Methazolamide50mgTabletsOral0.7040.361236.27−2.530.13−1.040.0961107.10
Methicillin40mg/mLSolutionInjection (i.v.)30088380.42−0.101.22−2.41−2.391.7862111.33
Methotrexate15mgTabletsOral0.450.181454.45−3.00−1.85−2.52−0.03−0.53125211.69
Methyldopa500mgTabletsOral100.240211.22−1.320.39−2.391.34−2.2654114.54
Methylnaltrexone20mg/mLSolutionInjection (s.c.)52.75356.45−1.12−1.12−1.70−2.644272.81
Metoclopramide10mgTabletsOral0.20.220299.80−3.182.620.32−1.252.234270.79
Metocurine iodide2mg/mLSolutionInjection (i.v.)350652.84−2.34−5.311.124055.25
Mezlocillin2000mgPowderInjection (i.v.)45539.59−3.361.5083184.12
Miglitol100mgTabletsOral80207.23−3.211.70−1.2665113.97
Miglustat100mgCapsulesOral10000.000485219.280.660.220.915491.41
Milnacipran100mgTabletsOral55246.361.461.912147.42
Milrinone1mg/mLSolutionInjection (i.v.)185211.23−2.320.68−2.50−0.033161.18
Mitoxantrone2mg/mLSolutionInjection (i.v.)7.57444.49−1.770.70−0.602.30108185.09
Morphine 6-glucuronideActive metabolite100090461.470.34−0.66−0.23−3.10105159.24
Moxifloxacin hydrochloride400mgTabletsOral27.50.0622401.44−1.20−0.83−0.087284.22
Nadolol160mgTabletsOral30.40.0273309.41−1.010.810.93−0.390.385491.35
Nafcillin sodium36mg/mLSolutionInjection (i.v.)27414.48−3.463.5352102.23
Naratriptan2.5mgTabletsOral350.000350335.47−0.98−0.721.703267.24
Neomycin B sulfate500mgTabletsOral6.30.340614.66−2.054.21−6.471913378.50
Neostigmine15mgTabletsOral1000.000667223.30−0.35−0.51−2.811028.55
Netilmicin100mg/mLSolutionInjection (i.v.)85475.592.52−2.40128215.91
Nizatidine300mgCapsulesOral21.650.0661331.46−1.18−0.201.00−2.55−0.166285.02
Nystatin200mgCapsulesOral40.2926.12−2.36−6.39−3.201712347.83
Ofloxacin400mgTabletsOral3.540.564361.38−2.01−0.39−0.40−0.57−0.517170.83
OlmesartanActive metabolite43446.51−2.312.5173127.62
Olopatadine hydrochloride5mgTabletsOphthalmic20.0165337.42−2.23−1.061.094151.11
OseltamivirActive metabolite99284.360.57−1.2453110.44
Oxacillin167mg/mLSolutionInjection (i.v.)46401.442.38−1.24−2.862.0552116.46
Palonosetron hydrochloride0.05mg/mLSolutionInjection (i.v.)40296.42−2.722.182020.62
Pamidronate disodium15mg/mLSolutionInjection (i.v.)46235.07−7.875.20−6.1786178.77
Pancuronium bromide2mg/mLSolutionInjection (i.v.)67572.88−4.271.212054.13
Pemetrexed disodium25mg/mLSolutionInjection (i.v.)9080427.42−0.68−2.23−1.1796198.63
Penciclovir10mg/gCreamTopical (skin, membranes)17075253.26−0.17−1.62−2.17−2.7264126.09
Penicillamine250mgCapsulesOral45149.21−1.78−3.942.60−1.733368.80
Penicillin G; benzylpenicillin39 (60,000mg/mL units/mL)Solution (as potassium salt)Injection (i.v.)334.401.83−1.81−2.211.754293.12
Pentostatin2mg/mLSolutionInjection (i.v.)3080268.27−0.95−2.09−4.65−1.17−1.9674111.17
Phenylethylmalonamide250mgTabletsOral79206.250.130.13−1.610.012292.49
Phenylpropanolamine75mgTabletsOral65151.210.83−2.270.990.582250.53
Pindolol10mgTabletsOral7.90.00554248.33−1.501.750.39−1.401.673360.21
Pipecuronium bromide1mg/mLSolutionInjection (i.v.)39602.91−3.570.634056.48
Piperacillin200mg/mLSolution (with 25 mg/mL tazobactam)Injection (i.v.)714.371517.560.140.50−3.30−3.441.7073164.86
Piperazine500mgTabletsOral2600.0085086.140.48−1.503.10−1.482229.15
Piracetam800mgTabletsOral70142.16−1.54−1.55−0.45−1.182165.69
Pirenzepine50mgTabletsOral500.00443351.41−0.850.10−0.39−3.12−0.355163.98
Plerixafor20mg/mLSolutionInjection (s.c.)1070502.80−1.704.68−0.258689.79
Potassium chloride1500mgTabletsOral333.30.028574.560.65−1.07−2.14000.00
Pramipexole1.5mgTabletsOral0.20.0390211.33−3.020.661.173252.49
Pravastatin80mgTabletsOral3000.00120424.54−0.152.18−0.23−3.752.0564135.57
Pregabalin300mgTabletsOral330.0490159.23−0.68−1.352.11−0.923268.80
Procainamide1000mgTabletsOral41.067235.33−1.770.88−1.15−0.521.423261.69
Pseudoephedrine120mgTablets (discontinued; 60 mg in combinations)Oral43165.241.130.800.892237.13
Pyridostigmine60mgTabletsOral1000.00285181.22−0.26−0.13−4.261029.12
Pyrimethamine25mgTabletsOral0.1210.865248.72−3.312.691.61−2.913.004275.82
QuinaprilatActive metabolite96410.47−0.501.9563115.68
Raltitrexed0.5mg/mLSolutionInjection (i.v.)50458.50−0.320.7184157.86
RamiprilatActive metabolite13388.47−0.281.7563115.68
Ranitidine300mgTabletsOral5550.00230314.410.250.270.54−1.500.675284.19
Regadenoson0.08mg/mLSolutionInjection (i.v.)0.0565390.36−3.89−3.00−2.86105181.70
Risedronate150mgTabletsOral87283.122.80−2.6285161.04
Ritodrine10mgTabletsOral10287.36−1.421.654482.87
Rocuronium bromide10mg/mLSolutionInjection (i.v.)17530.80−3.536.400059.59
Rolitetracycline250mgTabletsOral12500.000855527.580.37−3.21−0.820.47106184.85
Rosuvastatin calcium40mgTabletsOral5481.55−0.89−3.711.9083144.83
RoxatidineActive metabolite57.5306.40−2.622.354165.68
Saxagliptin5mgTabletsOral17.60.00124315.42−1.25−2.480.114288.67
Sitafloxacin50mgTabletsOral75409.82−1.33−1.2562120.37
Sitagliptin100mgTabletsOral78407.32−1.700.694171.38
Sotalol240mgTabletsOral1370.00785272.37−0.300.24−0.790.110.234388.93
Spectinomycin625mg/mLSolutionInjection (i.m.)7.570332.36−1.651.31−2.8895141.47
Stavudine40mgCapsulesOral830.00239224.22−0.430.14−1.60−0.494282.44
Streptomycin1000mgPowderInjection (i.m.)200.255581.58−1.462.10−4.261914357.04
Sulpiride200mgTabletsOral2.280.470341.43−2.180.57−1.15−0.991.1152108.62
Talinolol100mgTabletsOral1.230.352.8363.50−2.47−2.273.154493.35
Tazobactam sodium25mg/mLSolution (with 200 mg/mL piperacillin)Injection (i.v.)5077300.29−0.78−0.42−0.6571123.90
TemocaprilatActive metabolite29.5448.56−1.222.5663117.18
Temocillin disodium100mg/mLSolutionInjection (i.v.)414.46−1.321.5273142.75
Tenofovir disoproxil300mgTabletsOral13.40.0982519.45−1.591.25−3.710.80101176.07
Terbutaline5mgTabletsOral2130.0000956225.29−0.020.901.540.484482.87
Tetracycline25mg/mLSyrupOral1.758444.45−2.42−1.30−1.41−0.9196197.07
Tetracycline hydrochloride500mgCapsulesOral10.90.258480.94−1.64−1.30−1.410.66−0.9196197.07
Ticarcillin30mg/mLSolutionInjection (i.v.)100077384.430.42−1.171.2863133.95
Tigecycline10mg/mLSolutionInjection (i.v.)29522569.66−0.290.83−0.83105195.34
Tiludronic acid200mgTabletsOral60318.610.070.2664128.24
Tiotropium bromide18μgCapsulesOral74392.52−1.64−1.713158.42
Tirofiban hydrochloride0.05mg/mLSolutionInjection (i.v.)65440.61−2.342.0063116.61
Tobramycin40mg/mLSolutionInjection (i.v.)100093467.520.332.92−4.721410287.82
Tocainide600mgTabletsOral100.238192.26−1.280.760.83−0.940.262260.51
Topiramate200mgTabletsOral9.80.0870339.37−1.54−2.050.0481118.72
Topotecan1mgCapsulesOral10.00440421.46−2.62−0.910.7362102.76
Trimetazidine20mgTabletsOral62266.340.041.185143.06
Trimethoprim160mgTabletsOral1.370.570290.32−2.330.910.83−2.250.9872103.14
Triptorelin3.75mgPowderInjection (i.m.)41.71311.48−5.29−1.221718510.46
Trospium chloride20mgTabletsOral5000.00026392.520.11−3.50−1.162149.62
Tubocurarine3mg/mLSolutionInjection (i.v.)5063609.75−1.09−2.823.555283.96
Vancomycin250mgCapsulesOral500.02791449.29−1.46−7.43−1.142419584.97
Varenicline tartrate1mgTabletsOral0.20.0292211.27−3.02−0.280.903135.06
Vecuronium bromide2mg/mLSolutionInjection (i.v.)20557.84−3.704.333055.30
Vigabatrin500mgTabletsOral60129.16−2.16−2.602.68−2.223268.80
Vitamin B1 (thiamine)500mgTabletsOral270.0790265.36−0.99−1.58−5.974271.29
Zalcitabine0.75mgTabletsOral76.40.0000465211.22−0.44−1.30−1.64−1.24−1.255288.11
Zanamivir5mgPowderTopical (aerosol)180.001100332.32−1.271.76−5.56108215.70
Zoledronic acid0.8mg/mLSolutionInjection (i.v.)39272.093.16−3.0785161.62

Table IV

Measured and In Silico Data for 53 BDDCS Class 4 Drugs

Generic nameMaximum strength dose valueMaximum strength dose unitFormulationRouteMeasured solubility (mg/mL)Dose number% Excreted unchanged in urineMW drugMeasured LogS molarMeasured LogPMeasured LogD74minVSLgS 3–7.5CLogPHBAHBDPSA
Acetazolamide250mgTabletsOral0.641.690222.25−2.54−0.26−0.45−0.77−0.9852121.43
Acyclovir800mgTabletsOral2.51.375225.21−1.95−1.56−1.76−2.68−2.4263112.32
Amisulpride200mgTabletsOral50369.491.10−1.301.8062107.55
Atovaquone250mgTabletsOral3366.853.82−5.066.353159.10
Auranofin3mgCapsulesOral60678.49−1.913.7950117.05
Azapropazone; apazone300mgCapsulesOral0.06152060300.36−3.691.78−3.351.794052.35
CandesartanActive metabolite52440.47−2.115.4372114.16
Candesartan cilexetil32mgTabletsOral0.052.60610.68−4.09−4.357.3381136.25
Cefdinir300mgCapsulesOral15395.420.27−0.4884166.41
CefditorenActive metabolite70506.58−6.731.4692162.89
Cefixime400mgCapsulesOral0.055112941453.46−3.920.910.25104193.48
Cefpodoxime200mgTabletsOral81427.460.09−0.4193155.91
Cefprozil500mgTabletsOral0.0553673389.43−3.85−0.49−1.8764143.96
Ceftibuten400mgCapsulesOral0.082071410.43−3.711.68−1.2184171.87
Chlorothiazide500mgTabletsOral0.523.892295.72−2.75−0.24−1.10−1.59−1.0062126.91
Chlorthalidone100mgTabletsOral0.271.565338.77−3.100.850.85−2.980.4543120.90
Cinoxacin500mgTabletsOral60262.22−1.55−2.051.747191.03
Ciprofloxacin750mgTabletsOral0.152065331.35−3.340.28−1.21−0.45−0.736275.12
Clodronic acid800mgCapsulesOral0.3958.180244.89−2.794.95−0.1464128.24
Cloxacillin250mgTabletsOral0.01397275435.89−4.502.48−1.82−2.982.5252116.46
Dalfopristin100mg/mLSolutionInjection (i.v.)4.5690.86−5.350.9292177.78
DaunorubicinolActive metabolite25529.55−1.121.36116204.62
Enoxacin400mgTabletsOral0.62.745320.33−2.73−0.20−2.150.07−1.607285.36
Eprosartan600mgTabletsOral0.083030424.52−3.72−4.184.805292.48
Erythromycin stearate500mgTabletsOral0.336.151018.40−3.49−3.841.61135203.27
Felbamate600mgTabletsOral0.73.445238.25−2.53−0.29−1.930.5022110.07
Fleroxacin800mgTabletsOral0.873.772.5369.35−2.630.24−0.27−0.336161.72
FosinoprilatActive metabolite0.0143435.50−4.64−0.69−4.224.8552101.70
Furosemide80mgTabletsOral66330.752.03−1.54−2.381.9053130.02
Iopanoic acid; iodopanoic acid500mgTabletsOral0.01513333570.94−4.58−4.314.703268.50
Lenalidomide25mgCapsulesOral0.0004522266259.27−5.76−2.640.534288.83
Levocabastine0.5mg/mLSolutionOphthalmic70420.53−2.601.864160.70
Levonorgestrel0.75mgTabletsOral0.00142.152312.46−5.353.60−4.343.312140.83
Medroxyprogesterone acetate500mgTabletsOral0.0229144386.54−4.24−4.694.013063.61
Megestrol acetate40mgTabletsOral0.0028060384.52−5.28−4.573.583063.61
Meropenem333.3mg/mLSolutionInjection (i.v.)70383.470.11−3.2863116.86
Niclosamide500mgTabletsOral0.013154327.13−4.40−4.104.344299.56
Nitrofurantoin100mgCapsulesOral0.192.147238.16−3.10−0.47−0.19−1.74−0.4751118.74
Norfloxacin400mgTabletsOral0.752.129319.34−2.63−1.03−2.00−0.32−0.786275.12
Orlistat120mgCapsulesOral1495.75−7.638.613186.97
Paliperidone9mgTabletsOral0.011253.259426.50−4.582.52−2.771.125176.16
Penicillin V; phenoxymethylpenicillin500mgCapsulesOral0.258.0350.40−3.152.09−1.54−2.341.9452102.23
Phenazopyridine hydrochloride200mgTabletsOral41213.24−2.372.055288.00
Quinupristin100mg/mLSolutionInjection (i.v.)3.51021.26−6.157.05124236.20
Rifaximin550mgTabletsOral0.00122000.035785.90−5.90−7.167.24125205.94
Roxithromycin300mgTabletsOral0.11212837.07−3.922.75−4.952.29165224.19
Sulfadiazine500mgTabletsOral0.131557250.28−3.28−0.09−1.00−1.930.105299.95
Sulfamethizole500mgTabletsOral0.258.086270.33−3.030.54−1.11−1.900.4252102.86
Sulfisoxazole500mgTabletsOral0.131549267.31−3.311.01−0.87−2.010.2242102.81
TrandolaprilatActive metabolite402.49−0.722.3163115.68
Triclabendazole sulfoxideActive metabolite6.5375.66−4.524.361152.01
Valsartan320mgTabletsOral0.187.113435.53−3.38−4.774.8662113.69
Vitamin B2 (riboflavin)100mgTabletsOral0.113.675376.37−3.53−1.46−2.64−0.7395161.81

Table V

Measured and In Silico Data for 11 BDDCS Class 0 Drugs

Generic nameMaximum strength dose valueMaximum strength dose unitFormulationRouteMeasured solubility (mg/mL)Dose number% Excreted unchanged in urineMW drugMeasured LogS molarMeasured LogPMeasured LogD74minVSLgS 3–7.5CLogPHBAHBDPSA
Amphetamine sulfate10mgTabletsOral300.00140135.21−0.651.761.541.251.741127.97
Atracurium10mg/mLSolutionInjection (i.v.)8.5929.17−7.003.50100126.97
Chlorphentermine25mgTabletsOral17183.682.600.400.412.851127.97
Chlorpropamide250mgTabletsOral2.20.520276.74−2.102.27−0.13−2.662.353284.94
Cisatracurium besylate10mg/mLSolutionInjection (i.v.)8.5929.17−7.563.50100126.97
Dextroamphetamine15mgTabletsOral10.0640135.21−2.131.761.541.291.741127.97
Diethylcarbamazine citrate100mgTabletsOral63.70.00635199.30−0.501.08−0.691.622021.80
Mecamylamine2.5mgTabletsOral2120.0000550167.300.101.772.831114.57
Methamphetamine5mgTabletsOral10000.0000240149.240.830.991.891114.57
Phenmetrazine25mgTabletsOral2.519177.25−1.851.50−0.201.672123.37
Vitamin C; ascorbic acid1000mgCapsulesOral3330.0125176.130.28−1.850.92−1.7654117.30

Figure 3 depicts a box plot of the measured solubility values (representing about 68% of drugs listed in Tables I, ,II,II, III, and andIV)IV) used for assigning BDDCS classification. Class 2 and 4 drugs are less soluble than class 1 and 3 drugs, but there is a considerable overlap since the highest dose strength also affects the assignment. Further analysis with respect to the in silico predicted solubility values is addressed below.

Box plot of Log10 measured solubility values used for the BDDCS classification against BDDCS categories. Arrows pointing left show the mean, arrows pointing right the median; the shaded area indicates the 95% confidence interval, while the box itself is the interquartile range; the horizontal bars indicate the minimum and maximum values; squares are outliers. Class 1, −1.79 ± 1.27 (266 drugs); class 2, −4.29 ± 1.12 (166); class 3, −1.38 ± 1.18 (159); class 4, −3.70 ± 0.96 (35)

Percent Excreted Unchanged in the Urine (%Urine)

Although the FDA (4) and EMA (9) guidances list 90% and 85% absorption, respectively, as a cutoff for high permeability, Wu and Benet () believed that a 70% cutoff for BDDCS would be sufficient since the purpose of BDDCS was not to provide a regulatory exemption but rather to make a prediction of drug disposition. As noted above, Wu and Benet () found that there were very few drugs in which the percent of dose metabolized fell between 30% and 70%. One may be tempted to use the percent urine values in the tables to test this hypothesis, but this would be incorrect since a number of class 3 and class 4 drugs are known to be excreted unchanged in the bile, as are the metabolites of some class 2 and possibly class 1 drugs, depending on the BDDCS class of the metabolite. When a drug is given intravenously, the percent of drug unchanged in the urine is readily obtained. When for a given drug only the oral dosage forms are available, frequently limited human data may be available on a parenteral experimental formulation. In these two previous cases, that is the value listed in Tables I, ,II,II, III, and andIV.IV. Where only oral human data are available, the authors used their best judgment in correcting the value with a bioavailability parameter. Lowering the cutoff to 70% obviates in most cases any error that would be inherent in classification based on this assumption. However, the criterion for poor metabolism in BDDCS is excretion of unchanged drug both in the urine and in the bile. The extent of biliary excretion of unchanged drug is an experimentally difficult value to obtain in humans for most drugs. But this is the criterion that we have used in the assignment of BDDCS classification for the more than 900 drugs listed in the tables. It will be obvious in reviewing Tables III and andIVIV that a number of class 3 and class 4 compounds show very low values for %Urine. For example, erythromycin is listed in Table III with 4% excreted unchanged in the urine; however, only 15% of an erythromycin dose is metabolized with more than 80% excreted unchanged in the bile. Thus, for the class 1 and 2 drugs in Tables I and andII,II, the low percent urine does reflect fairly accurately the degree of metabolism since for these compounds it is usually the metabolites that are excreted into the bile, not the parent drug. However, for the class 3 and the class 4 compounds, the assignment was not made based only on the percent urine data value in Tables III and andIV.IV. The box plot depicted in Fig. 4 reflects these differences between classes 1 and 2 versus classes 3 and 4, with the very wide standard deviations below the mean for classes 3 and 4 reflecting the importance of biliary excretion in these assignments.

Box plot of%Urine against BDDCS. Key: as in Fig. 3. Class 1, 5.3 ± 6.8 (303); class 2, 3.4 ± 6.3 (227); class 3, 61.3 ± 24.4 (243); class 4, 47.8 ± 27.1 (50)

As mentioned earlier, Benet et al. () proposed that ≥90% metabolism could be an additional criterion that regulatory agencies may use in confirming that a drug was more than 90% absorbed. In that paper, Benet et al. () restricted the metabolic processes to those that would only occur following absorption such as cytochrome P450 metabolism or metabolism by phase II enzymes found in the gut or the liver. However, in the present compilation, the metabolism criterion for BDDCS assignment does not limit the metabolic processes to these enzymes only. In the present tables, when a drug is metabolized 70% or more, it is classified as highly metabolized and if the metabolism is <70% is categorized as poorly metabolized (readers will note in Fig. 4 that five class 1 and 2 drugs show between >30% and ≤40% excreted unchanged. For these compounds, it is the authors’ belief that these drugs operate more like the assignment made).

Maximum Strength Dose

For US-approved drugs, the maximum dose strength is taken from the package insert. In a number of cases, we have included drugs in the tables that have been removed from the market and drug products where a package insert was not available. In those cases, the maximum strength dose was selected based on an evaluation of literature data.

Figure 5 is a box plot of the −Log10 of the maximum strength dose (molar) against BDDCS. It appears that class 4 drugs have the highest dose (molar) compared with other BDDCS classes, whereas class 1 drugs have the lowest strength. This most likely relates to differences in bioavailability, but may also relate to differences in efficacy. The more lipophilic highly metabolized drugs tend to be more active toward wanted and off targets because of a higher capability of nonspecific interactions. Therefore, it is more likely that drugs that are less lipophilic and less metabolized are given at a higher dose since they are probably less potent and since there is less risk of toxicity.

Box plot of the −Log10 of the maximum strength dose (molar) against BDDCS. Key: as in Fig. 3. Class 1, 4.12 ± 1.01 (288); class 2, 3.79 ± 0.97 (236); class 3, 3.67 ± 1.13 (163); class 4, 3.24 ± 0.69 (43)

BDDCS Classification and Dose Number

High versus low solubility was determined using the FDA/EMA criteria of the maximum strength dose of the drug at its lowest solubility over the pH range of 1–7.5 being soluble in 250 mL of water at 37°C. The solubility cutoff may be expressed as the dose number, which is calculated as the highest dose strength (milligrams) divided by 250 mL and the lowest solubility (milligrams per milliliter). When the dose number is ≤1.0, the drug is considered to have high solubility; when the dose number is >1.0, the drug is considered to have low solubility. Using the solubility (dose number) and the percent metabolism criteria discussed above, the BDDCS class was assigned. For non-orally dosed drugs and active metabolites, no dose number is given in the tables, and the BDDCS assignment is based on the best estimate of the relevant solubility as determined by the authors. This opens the possibility of a more refined system, the dose-dependent BDDCS, dBDDCS. Such a system, based on evaluating multiple strength doses, could highlight “class migration,” which is likely to occur for some drugs, versus “class propensity.” We anticipate that some drugs will migrate to a neighboring class depending on dose strength, whereas most drugs, however, are likely to show preference for one class only. By migrating existing class 4 drugs toward class 3 or class 2 drugs toward class 1, one is likely to obtain improved biopharmaceutical characteristics; thus, FDA approval for novel formulations can be requested using a drug repurposing mechanism () under Section 505(b) () of the Federal Food, Drugs and Cosmetic Act.

Bcs Classification Database

Class Zero

For a number of drugs, such as amphetamine, changes in urinary pH affect the extent of metabolism. Therefore, it is not possible to assign a BDDCS class. It appears for the 11 drugs listed in Table V that they all are predominantly highly soluble in water and thus would probably be BCS class 1 drugs, or BDDCS class 1 or class 3 depending upon urine pH.

MLogP and MLogD7.4

When no active transport processes are involved, pharmaceutical scientists expect lipid/water partition coefficients to be correlated with drug permeability. The Lipinski Rule of Five (–) was an attempt to define the upper limits of lipophilicity for developing NMEs that are likely to be orally available. As noted above, Takagi et al. () evaluated the correlation of measured LogP and calculated LogP with BCS high versus low human jejunal permeability rate compounds, finding that the correlation only held about two thirds of the time. Since there is interest in these parameters and following our guideline of attempting to use measured experimental values when available in making predictions, we have included in Tables I, ,II,II, III, ,IV,IV, and andVV values for measured LogP and measured LogD at pH 7.4 when such values are available. Again, individual references for the values are not included. However, in the section below, we will comment on prediction differences and accuracy with respect to in silico calculations. Figure 6 is a box plot of the measured LogD values at pH 7.4 against BDDCS assignment.

Box plot of MLogD7.4 values against BDDCS. MLogD7.4 for class 2, 2.11 ± 1.91 (121) is the highest among all classes. Class 1, 1.24 ± 1.68 (220); class 3, −1.26 ± 2.19 (110); and class 4 −0.42 ± 1.77 (20). Key: as in Fig. 3

This provides some partial explanation for the food effects mentioned earlier. BDDCS class 2 drugs have high-fat solubility, as illustrated by their higher measured LogD7.4 (Fig. 6), compared with other classes. Under high-fat meal conditions, higher amounts of drug are therefore likely to be solubilized in the intestinal contents and become available to the enterocytes for (passive) absorption. However, we do not see a similar effect for the more hydrophilic, poorly soluble class 4 drugs. Since BDDCS class 1 drugs already are solubilized, they would receive no benefit from increased lipid solubilization.

IN SILICO PARAMETERS

As discussed above, BDDCS assignments were based on the measured parameters of extent of metabolism and solubility, although in the latter case, for extremely poorly soluble and very highly soluble compounds, a numerical value is not always available. However, it is also useful to analyze how well or how poorly in silico parameters can predict the BDDCS classification and to use this type of computation to make other predictions. Thus, for each compound in the tables, we also include: the molecular weight of the listed compound; the calculated LogP (CLogP) using the method of Leo (40); the number of hydrogen bond donors (HDo) for the active moiety; the number of hydrogen bond acceptors (HAc) for the active moiety; the polar surface area (PSA) calculated using the method of Clark (); and the log of the lowest water solubility calculated over the pH range 3–7.5 (minVSLgS; VolSurf+), as proposed by Cruciani et al. (42,43). We also calculated (and list in Supporting Info) the solubility of each drug in its neutral form using Tetko’s solubility in water (TLogSw) prediction using ALOGPS 2.1 [see ()]. We hope that this parameter compilation and discussion will be valuable to investigators trying to develop better prediction methods.

Solubility and Dose Number

Both in silico solubility predictions correlate poorly with the measured values, although the VolSurf+ correlation (r2 = 0.33) is somewhat better than the ALOGPS solubility (r2 = 0.24). However, even with these poor correlations, the predicted dose numbers (cDose Number) with the calculated VolSurf+ solubility were reasonable for class 1, 2, and 3 drugs. Results for the VolSurf+ (and ALOGPS) solubilities were as follows: Class 1 drugs are classified with an accuracy of 78.6% (54.3%), class 2 with an accuracy of 76.9% (84.3%), and class 3 with accuracy of 89.4% (65.7%). The predictive accuracy for class 4 drugs was very poor (39.5%) for the VolSurf+ prediction, but reasonable when the pH effect is not considered (79.1% when using ALOGPS). Upon further examination, 17 of these drugs are well predicted by cDose Number. These 17 drugs have a “class2-like” CLogP profile (average CLogP = 3.76). The deviation between measured LogS and minVSLgS is on average 0.66 for these drugs. For the 26 class 4 drugs that are poorly predicted, the average CLogP is 0.27, and the average measured LogP is 0.11. The deviation between measured LogS and minVSLgS is on average around 3.00. A number of these 26 drugs are likely to exist as zwitterions at pH below 7.5; several among them are fluoroquinolone antibiotics. In particular, for enoxacin, ciprofloxacin, norfloxacin, and cinoxacin, solubility prediction based on melting point and LogD failed, probably due to self-association (45). In support of this hypothesis, Ross and Riley (45) noted that the solubility of these drugs at the same pH increases with temperature. The lowest measured solubility data for class 4 drugs are observed when these molecules behave as zwitterions (pH 7). Therefore, the reason for class 4 assignment prediction error is likely to relate to self-association for drugs that behave as zwitterions. This is less likely to play a role in the digestive tract since varying pH conditions, the presence of counterions, and surfactants (e.g., bile acids) might diminish the importance of self-association. Despite the relatively high success of the ALOGPS method for class 4, solubility predictions for these zwitterions in neutral form, which essentially ignores the pH effect, should be used with caution.

Partition Coefficient and Extent of Metabolism

As discussed above, a high extent of metabolism is expected for high LogP compounds and vice versa. In contrast to the predicted versus measured solubility values discussed above, the correlation between MLogP versus CLogP is quite good (r2 = 0.83). Thus, it might be expected that both MLogP and CLogP would reasonably well predict class 1 and 2 drugs versus class 3 and 4 drugs, with the results shown in Fig. 7. For either measured or calculated LogP > 2, the probability of extensive metabolism is 80.1% and 79.3%, respectively. For LogP values <0, the probability of poor metabolism is 83.5% for MLogP and 83.9% for CLogP. However, when LogP values range from 0 to 2 (31.7% of drugs for MLogP and 27.5% of drugs for CLogP), the probability assignments are not very good, with MLogP doing somewhat better for extensively metabolized drugs and CLogP doing somewhat better for poorly metabolized drugs (Fig. 7). As with solubility predictions, the poorest probability of extent of metabolism was found for class 4 drugs (data not shown).

Probability of extensive metabolism in different measured LogP and CLogP ranges. The plot show the probability of being extensively metabolized in a specific LogP (CLogP) range if a set with equal number of extensively and poorly metabolized drugs is considered

Summary of In Silico Parameters for Orally Dosed Drugs

Figure 8 highlights the in silico parameters for 698 orally dosed drugs. As expected, CLogP is higher and PSA lower for extensively metabolized (class 1 and 2) drugs. However, an unexpected finding is the very marked similarity for solubility and (somewhat less) for CLogP predictions for class 1 and 4 drugs. This reflects the inherent confounding aspects of the dose number calculation used in both BDDCS and BCS, as discussed earlier in this manuscript and by Rinaki et al. (), and the generally poor predictability for class 4 drugs. We also calculated the polar surface area density (PSAD = MW/PSA) and are struck by the empirical observation of the similarity and low coefficient of variation for PSAD (Fig. 8) for the class 3 and class 4 poorly metabolized drugs. As noted by the arrows in Fig. 8, class 2 and class 3 drugs exhibit the extremes for the in silico measures of solubility and partition coefficient.

In silico parameters for 698 orally dosed drugs. For each, calculated property average value and standard deviation are shown. PSAD (polar surface area density) = MW/PSA

OTHER COMMENTS

Bcs

The listing of drugs in the five tables is essentially inclusive of small molecules only as most peptide and protein drugs were not included in the compilation. However, there are exceptions, such as the inclusion of exenatide and liraglutide. We note that all the drugs listed in the 2011 Goodman and Gilman compilation (47) are included in the present table except, for streptokinase and interferon alpha and beta. Since many drugs on the market are in fact pro-drugs, when data were available, our listing includes the parameters for some of the better characterized active metabolites, even when the metabolite itself was not a commercially available product and thus the maximum strength dose does not exist. For example, see flurazepam and desalkylflurazepam (both Table I) as well as losartan (Table II) and EXP3174 (Table III). In those cases, the BDDCS classification was made based on the dose of the parent drug, the known fraction conversion to the active species, and the solubility of the active metabolite. The finding of Wu and Benet () that very few drugs fall in the 30–70% metabolism range does not mean that there are no such drugs. For example, in Table III, moxifloxacin HCl has been shown to be metabolized 52% (14% as a glucuronide and 38% as a sulfate conjugate) while 45% is excreted unchanged (25% in the feces and 20% in the urine). Similarly, palonosetron HCl (Table III) is excreted 40% unchanged and 50% via CYP enzymes, while phenazopyridine (Table IV) is excreted 41% unchanged and 49% metabolized.

WHERE CAN ADDITIONAL INFORMATION BE FOUND?

Oprea and co-workers (48,49) have indexed the information for over 1,260 drugs in WOMBAT-PK, a database that includes pharmacokinetic parameters (such as those indexed in Goodman–Gilman), physicochemical properties, and target bioactivities (see http://www.sunsetmolecular.com/index.php?option=com_content&view=article&id=16&Itemid=11). WOMBAT-PK contains additional information related to the BDDCS entries described in the tables. However, all pertinent data used to categorize individual drugs for the BDDCS classification are provided here. Further information about drugs can also be found in public resources as follows: Chemical information, physicochemical properties, and bioactivities are compiled in PubChem (http://pubchem.ncbi.nlm.nih.gov/), ChEMBL (https://www.ebi.ac.uk/chembl/), and ChemSpider (http://www.chemspider.com/). Detailed drug information can be retrieved at DailyMed (http://dailymed.nlm.nih.gov/dailymed/about.cfm), DrugBank (http://drugbank.ca/), and European Medicines Agency (http://www.ema.europa.eu/).

Information as found in the five tables, together with the physicochemical properties and target bioactivities, can serve as a source for investigating and predicting the characteristics of NMEs in drug development. However, we add a further caution concerning in silico methodologies that may be developed based on our compilation of data for drugs on the market at some time. This is illustrated in Fig. 9 where we have compiled the BDDCS classification of the orally dosed drugs in our tables. In Fig. 9, we compare this distribution of commercially available drugs with our predictions of the distribution of total NMEs that have at some time been dosed to humans, particularly in the last decade. Based on our prior evaluation of high-activity medicinal chemistry compounds (), we estimate that of the drug candidates being investigated by the industry, up to 70% are large molecular weight, lipophilic, poorly soluble class 2 compounds, another 20% are not only poorly soluble but also poorly permeable class 4 compounds, while only 10% are high-soluble class 1 and class 3 compounds. Thus, when in silico methodologies are developed and tested on commercially available drugs, it is important to remember that 40% of drugs are BDDCS class 1, and as predicted in Fig. 2, these compounds will not exhibit disposition characteristics affected by transporters in the gut and liver, whereas up to 95% of NMEs are likely to be affected. Therefore, in testing such new methodologies, it is critical that both the training and test compound sets have a strong representation of compounds other than BDDCS class 1.

BDDCS distribution of 698 marketed, immediate release, orally dosed drugs in the present table versus the predicted distribution of small molecule NMEs being developed by the industry

ELECTRONIC SUPPLEMENTARY MATERIAL

Below is the link to the electronic supplementary material.

Acknowledgments

The authors were supported in part in preparation of the five tables and this manuscript by NIH grants GM-61390, GM-75900 and GM-90457 (LZB), and by GM-095952, MH-084690, and CA-118100 (TIO). We thank Molecular Discovery Ltd. and Professor Cruciani for the VolSurf+ suite license.

Supporting Info Available

Bcs Classification Of Drugs

An excel file is available as supporting info containing the following data for the 927 drugs dataset: name, BDDCS class, max dose strength value, max dose strength unit, formulation, route, measured solubility, dose number, % excreted unchanged in urine, MW drug, MW solution, pDose, measured LogS molar, measured LogP, measured LogD7.4, ALOGPS 2.1 solubility, cDose Number (ALOGPS based), minVSLgS, cDose Number (minVSLgS based), cLogP, HBA,HBD, PSA, and violations to Rules of Five. Definitions for the terms used only in the supporting info file may be found at the end of that data set. In addition, box plots of minVSLgS, ALOGPS 2.1 solubility, MLogP, cLogP, MW, PSA parameters against BDDCS are provided.

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