83

DARU Vol. 19, No. 2 2011

Evaluation of the use of partition coefficients and molecular surface

properties as predictors of drug absorption: a provisional biopharmaceutical
classification of the list of national essential medicines of Pakistan
*
Shawahna R. Rahman NU.

Department of Pharmacy, Faculty of Pharmacy and Alternative Medicine, The Islamia

University of Bahawalpur, Pakistan.

Received 15 Dec 2010; 22 March 2011; Accepted 25 March 2011

ABSTRACT
Background and the purpose of the study: Partition coefficients (log D and log P) and molecular
surface area (PSA) are potential predictors of the intestinal permeability of drugs. The aim of
this investigation was to evaluate and compare these intestinal permeability indicators.
Methods: Aqueous solubility data were obtained from literature or calculated using ACD/Labs and
ALOGPS. Permeability data were predicted based on log P, log D at pH 6.0 (log D6.0), and PSA.
Results: Metoprolols log P, log D6.0 and a PSA of <65 correctly predicted 55.9%, 50.8%
and 54.2% of permeability classes, respectively. Labetalols log P, log D6.0, and PSA correctly
predicted 54.2%, 64.4% and 61% of permeability classes, respectively. Log D6.0 correlated well
(81%) with Caco-2 permeability (Papp). Of the list of national essential medicines, 135 orally
administered drugs were classified into biopharmaceutical classification system (BCS). Of these,
57 (42.2%), 28 (20.7%), 44 (32.6%), and 6 (4.4%) were class I, II, III and IV respectively.
Conclusion: Log D6.0 showed better prediction capability than log P. Metoprolol as permeability
internal standard was more conservative than labetalol.
Keywords: Biopharmaceutical classification system, Permeability, log P, log D, PSA.

INTRODUCTION avoidance of risk presented to human volunteers

Systemic bioavailability of an orally administered usually encountered in the bioequivalence
drug is largely dependent on its physicochemical studies (4). Molecular surface properties and
properties and dosage formulation factors (1). partition coefficients have been used actively
Sophisticated modeling of the kinetics and in construction of quantitative structure activity
dynamics of drug processes in the gastrointestinal relationship (QSAR) models to predict intestinal
tract subsequently led to the advent of the permeability (2, 5-6).
biopharmaceutical classification system (BCS) (2). This study reports for the first time an evaluation and
According to the biowaiver, any possible variation comparison of pH-dependent and pH-independent
in the bioavailability of a rapidly dissolving and n-octanol/water partition coefficients (log D and
highly soluble drug is attributed to physiological log P) and polar surface area (PSA) in prediction
conditions rather than formulation and hence there of intestinal permeability of drugs. The log D at
is no logic in conducting a bioequivalence testing physiologically relevant pH of 6.0 (log D6.0) was
for such formulation (2). BCS offers a framework used to provisionally classify the orally administered
for development of pharmaceutical formulations. drugs on the list of national essential medicines
It has been estimated that the pharmaceutical (NEML) of Pakistan into BCS.
industry can save $35 million annually through
the applications of BCS (3). Assignment of the MATERIAL AND METHODS
solubility and permeability classes of a drug is The present revision of the NEML contains 335
a laborious task. Lately, computational models medicines of different pharmacological classes (7).
to predict aqueous solubility and permeability The highest dose of drug products available in oral
through biological membranes have received dosage forms, i.e. oral tablets and capsules, were
considerable attention. The use of physicochemical used.
properties in predicting in vivo behavior of drugs
has many advantages including cost reduction; Solubility
better control over protocol, reproducibility and The dose number (Do) was calculated using equation 1:

Correspondence: ramzi_shawahna@hotmail.com
 Partition coefficients and molecular surface properties as predictors of drug absorption 84

Mo/Vo class assignment was compared to the WHO

Do = (1) solubility classification (16). Of the 80 drugs in
Cs
common, 66 drugs (82.5%) were classified in the
same solubility classes, whereas, of the 14 drugs
Where Mo is the highest dose strength (in mg), Cs is for which the solubility classes were different,
the solubility (mg/ml), and Vo equals to 250 ml (8). 6 drugs were classified based on incomplete/
The most conservative data measures were used and inconclusive data and 3 drugs had higher or lower
experimental aqueous solubility data triumphed over doses on the NEML as compared to the WHOs
predicted data. Experimental solubility data were EML (Supplementary table 2).
obtained from Yalkowsky & He (9) and Drugbank Of the 135 drugs on the NEML, 15 (11.1%) drugs
(10) which in the later, data were originally from were classified according to their experimental
(11). Data reporting the pH and temperature at solubility data obtained from Yalkowsky & He, of
which the aqueous solubility of the compound was which 7 (46.7%) were classified as high soluble drug
measured were favored. Solubility data for the while the rest of 8 (53.3%) were classified as low
rest of the drugs were calculated using ACD/Labs soluble drugs. Additionally, 33 drugs (24.4%) were
(ACD/Labs, version 6.0; Advanced Chemistry classified based on the solubility data obtained from
Development: Toronto, Canada) and ALOGPS Drugbank. Of these, 29 (87.9%) were classified as
(ALOGPS, version 2.1. The Virtual Computational high solubility drugs while the rest of 4 (12.1%)
Chemistry Laboratory, VCCLAB, Germany). The were classified as low soluble drugs. The rest of
ionization constant (pKa) values were obtained from 87 drugs (64.4%) were classified according to the
the literature (12). ACD/Labs predicted soluble, of which, 66 (75.9%)
were classified as high soluble drugs and 21 (24.1%)
Permeability drug were assigned to low solubility class drugs
Log D and log P are linked through the equations 2 (Table 1).
and 3:
For acids: Permeability correlation and class assignment
Kasim and colleagues used metoprolol as internal
Log D= Log P - Log (1+10 pH-pKa) (2) standard indicating high permeability (14). Palm
and colleagues showed that PSA of <60 ensured
For bases: complete intestinal absorption (6); however, Kelder
and colleagues showed drug intestinal permeation
Log D= Log P - Log (1+10 pKa-pKa) (3) predominated by passive diffusion and paracellular
route for drugs with PSA of less than 120 (17).
Both log P and log D values were calculated using When log D6.0 of -1.48, log P of 1.35, and a relaxed
ACD/Labs. Similarly, PSA values were estimated PSA of 65 were used to indicate high permeability
using ACD/Labs. of the 59 drugs in common with the Lindenbergs
list, cutoffs correctly predicted the permeability class
RESULTS AND DISCUSSION of 30, 33 and 32 drugs (50.8%, 54.2% and 55.9%),
Previously the orally administered drugs on the respectively (Supplementary table 3). The fraction
World Health Organization (WHO) essential absorbed (Fa) of metoprolol (95%) is considerably
medicine list (EML) were provisionally classified even more conservative than permeability criteria
into BCS (13-14). The NEML contained 135 orally (90%) of the Food and Drug Administration (FDA)
administered drugs. It has been emphasized that (18). The use of labetalol as high permeable internal
the maximal administered dose to solubility ratio standard (Fa 90%) was evaluated using log D6.0 of
has a central role in the BCS (15). The NEML -0.42, Log P of 2.31, and PSA of 95.6 . These
contained 89 drugs in common with the WHOs cutoffs correctly predicted the permeability class
EML while in term of doses, only 46 were similar of 38, 32, and 36 drugs (64.4%, 54.2% and 61%),
(Table 1). respectively.
When WHOs classification (16) where compared
Solubility correlation and class assignment with the current classification in table 1; of the 80
Lindenberg and colleagues classified 61 drugs drugs in common, 62 drugs (77.5%) were classified
with certainty on the basis of reliable practical in the same permeability classes, whereas, of the
solubility data. A total of 59 drugs were in common 18 drugs for which the permeability classes were
with Lindenbergs list (13). ACD/Labs calculated different, 11 could be correctly classified by their
solubility and predicted correctly that 51 (86.4%) PSA values (Supplementary table 2).
of the solubility classes; whereas, data obtained To further verify the suitability of the permeability
from Drugbank and ALOGPS could correctly class assignment based on log D6.0, the Caco-2
predict 76.3% and 78% of the drugs classified, monolayer permeability (Papp) values for a total of 22
respectively (Supplementary table 1). Solubility drugs which were in common with a previous work
 Shawahna et al / DARU 2011 19 (2) 83-99 85

Permeability

Solubility

Figure 1. Biopharmaceutical classification system with drugs on the list of national essential medicines of Pakistan.

(13) were obtained; these values were basically conservative since the solubility usually increases as
compiled from the literature. The Papp value for a function of temperature, therefore, the solubility
labetalol was obtained from literature (15). Log values at 37C would be higher than the values used.
D6.0 correctly predicted the permeability class for In vivo human permeability investigations are
18 (81.8%) of the 22 drugs (Supplementary table expensive in terms of financial resources and
4). Furosemide, hydrochlorthiazide, saquinavir, technical allocations; and moreover are time
and sulphasalazine were false positives. Similarly, consuming. Several reports described a certain
the PSA of 95.6 (PSA of labetalol) correctly correlation between physicochemical properties
predicted the permeability class for 18 (81.8%) of of drug molecules with intestinal absorption (6,
the 22 drugs (Supplementary table 4). Acetylsalicylic 19-22). Linnankoski and colleagues suggested
acid, atenolol and zidovudine were false positives, that passive diffusion predominates the routes of
whereas, digoxin was a false negative. The PSA intestinal administration for the majority of the
of 65 correctly predicted only 15 (68.2%) out drugs (20). Although influx and efflux transporters
of the 22 drugs compared. In the study of Kasim have an important role in the absorption of some
and colleagues, the log P of metoprolol correctly drugs, interestingly, for the majority of drugs the
predicted 18 of 28 (64%) drugs (5). active transport is actually negligible (20). Most
The permeability classes were assigned using log of the drugs available in the market are ionizable
D6.0 in comparison to labetalol which was used as molecules; therefore, passive diffusion of these
internal standard. In this classification, 128 (94.8%) ionizable drugs is partly governed by their pKa
of the 135 drugs on the NEML were classified, of values. Consequently, log D at physiologically
these, 83 (64.8%) were assigned in high permeability, relevant pH should better reflect the overall
while the rest of 45 (35.2%) were assigned in low distribution (ionized and unionized) of a drug (22,
permeability classes. The rest of the 7 (5.2%) were 23).
classified according to their PSA values. Of these 2 Recently, labetalol was suggested as a better internal
(28.6%) were classified as high permeability drugs, standard in the permeability comparisons (24). The
while the rest of 5 (71.4%) were classified as low effective intestinal permeability (Papp) is typically
permeability drugs. The final BCS classification of the parameter reflecting both the rate and extent of
the 135 orally administered drugs on the NEML is intestinal absorption. In the current classification,
given in table 1 and class distribution is shown in labetalol was used as internal standard. In accordance
figure 1. with results of this study, Winiwater and colleagues
Literature often reported solubility data at room found a correlation between Papp, log D at pH of 5.5,
temperature. In contrast, the current solubility PSA and hydrogen bond donors, the use of log D6.0
classification methodology yielded an acceptable gave better predictions than log P (22). Similarly,
accuracy of 86.4% and 78.3% for ACD/Labs and Linnankoski and colleagues established a correlation
Drugbank solubility values respectively. Moreover, between the intestinal absorption rate constant (Ka)
the current classification of solubility criteria were with log D6.0 and PSA (20).
 Partition coefficients and molecular surface properties as predictors of drug absorption 86

Table 1. BCS classification of the orally administered drugs on the list of national essential medicines (NEML) of Pakistan with their
therapeutic classes, maximum doses, experimental water solubility, predicted aqueous solubility (ACD/Labs), pH dependent solubility (pKa),
log D6.0, calculated PSA, and interaction with transporters in the intestine.

Provisional biopharmaceutical classification of drugs on the list of national essential medicines (NEML) of Pakistan.

Solubility Permeability BCS classification

pKa
Maximum Log Transporters Solubility Permeability BCS
Drug Therapeutic class Do1 Do2 Do3 PSA
dose (mg) D6.0 interaction class class Class
HA
BH+

Acetylsalicylic acid NSAID 300 NA 0.0012 3.48 -1.24 63.6 Pgp High Low III

Acyclovir Antiviral 200 NA 2.1 9.18 1.89 -1.76 109.83 OATP1, OATP3, OCT1 Low Low IV

Albendazole Anthelmintic 200 NA 13.3 10.46 5.62 2.87 92.31 BCRP Low High II

Allopurinol anti-gout 300 NA 0.03 9.2 2.4 -3.81 74.69 NA High Low III

Amiloride Diuretic 5 NA 0.16 8.58 1.58 1.07 156.79 NA High High I

Aminophylline Antiasthmatic 200 NA 0.00002 NA NA 192 NA High Low III

Amiodarone Antiarrhythmic 200 1.1 9.37 6.29 42.7 MDR1 Low High II

Amitryptyline Antipsychotic 50 NA 0.14 9.24 2.08 3.24 NA High High I

Amlodipine Antihypertensive 5 NA 0.001 8.73 1.43 99.9 MDR1 High High I

Amoxicillin Antibacterial 500 NA 6.66 2.61 6.93 -1.93 158.26 PEPT1 Low Low IV

Amphotericin B Antifungal 100 0.5 3.96 8.13 NA 320 NA High Low III

Ampicillin Antibacterial 500 0.2 2.61 6.79 -1.21 138 PEPT1, OCTN2 High Low III

Anastrozole Anticancer 1 NA 0.008 4.78 0.77 78.3 NA High High I

Atenolol Antihypertensive 100 NA 0.0004 13.88 9.17 -2.73 84.58 MDR1 High Low III

Atropine sulphate Antispasmodic 1 NA 6.76E-06 9.88 -1.52 49.77 NA High Low III

Azathioprine Anticancer 50 1.5 0.25 -0.54 143 NA Low Low IV

Bromocriptine Antiparkinsonism 2.5 NA 0.11 9.61 6.45 4.52 118 MDR1 High High I

Busulphan Anticancer 0.5 NA 1.20E-07 NA -0.52 104 NA High Low III

Baptopril Antihypertensive 50 NA 0.0002 3.82 -2.02 96.41 MDR1: PEPT1 High Low III

Carbamazepine Antiepileptic 200 NA 10 13.94 2.67 46.33 MDR1 Low High II

Carbidopa Antiparkinsonism 25 NA 0.1 3.4 7.91 -2.71 116 NA High Low III

Cefixime Antibacterial 100 NA 0.03 2.1 2.86 -3.72 238 NA High Low III

Cefuroxime Antibacterial 250 NA 3.52 2.59 -4.47 199 PEPT1 Low Low IV

PEPT1, PEPT2,
Cephalexin Antibacterial 500 0.04 3.12 6.8 -2.22 138 High Low III
OCTN2

Cephradine Antibacterial 500 0.25 3.12 6.99 -1.53 138 OAT1, OCTN2, PEPT1 High Low III

Chlorambucil Anticancer 2 0.01 4.86 3.66 1.52 40.5 MRP1 High High I

Chloramphenicol Antibacterial 250 NA 4.3 11.03 1.02 115.38 NA Low High II

Chloroquine Antimalarial 150 NA 0.02 10.48 1.2 28.16 MDR1 High High I
 Shawahna et al / DARU 2011 19 (2) 83-99 87

Table 1 (Cont)
Solubility Permeability BCS classification

pKa
Maximum Log Transporters Solubility Permeability BCS
Drug Therapeutic class Do1 Do2 Do3 PSA
dose (mg) HA BH+ D6.0 interaction class class Class

Chlorpheniramine Antiallergic 4 NA 0.0003 9.33 0.49 16.13 NA High High I

Chlorpromazine Antipsychotic 100 NA 0.44 9.43 2.28 31.78 MDR1, OCT1 High High I

MDR1, OAT1, OAT3,

Cimetidine Antiulcer 400 NA 0.14 6.73 -1.14 114.19 High Low III
OCT1, OCT3, OCTN2

Ciprofloxacin Antibacterial 250 NA 0.77 2.74 8.76 -1.07 72.88 MDR1 High Low III

Clofazimine Antileprosy 100 NA 412.4 6.24 5.72 39.99 MDR1 Low High II

Clomipramine Antipsychotic 25 NA 0.09 9.49 2.58 6.48 MDR1 High High I

Clofazimine Antileprosy 100 NA 412.4 6.24 5.72 39.99 MDR1 Low High II

Cloxacillin Antibacterial 250 NA 0.07 NA -0.81 138.04 PEPT1 High Low III

Colchicine anti-gout 0.5 NA 0.03 NA 0.92 83.09 MDR1, OCT3 High High I

Cyclizine Antihistamine 50 NA 0.2 7.46 1.83 6.5 NA High High I

Cyclophosphamide Anticancer 50 NA 0.002 4.09 0.23 51.38 MDR1 High High I

BCRP, MDR1, MRPs,

Cyclosporin Immunosuppressent 100 10 NA NA 279 Low Low IV
OATP1B1

Dapsone Antileprosy 50 NA 0.57 1.24 0.94 94.56 NA High High I

Dexamethasone Antiallergic 0.5 NA 0.04 12.14 1.87 94.83 MDR1, OATP1A2 High High I

Diazepam Sedative 10 NA 2 3.4 2.96 32.67 MDR1 Low High II

Didanosine (ddi) Antiretroviral 400 NA 0.81 8.67 1.98 -1.33 83.81 NA High Low III

MDR1, OATP1B3,
Digoxin Cardiostimulant 0.25 NA 0.002 13.5 0.85 203.06 High High I
OATP1C1, OATP4C1, OST

Diloxanide Anti-Amoebic 500 NA 1.08 NA 1.62 40.54 NA Low High II

Calcium channel
Diltiazem 180 NA 0.006 8.91 2.64 84.4 MDR1 High High I
blocker

Doxycycline Antibacterial 100 NA 0.54 4.5 9.32 -3.06 181.62 OAT1, OAT3, OAT4 High Low III

Efavirenz Antiretroviral 50 NA 376.6 7.92 4.84 38.33 NA Low High II

MDR1,
Enalapril Antihypertensive 10 NA 0.002 3.75 5.5 -0.12 95.9 High High I
OATP1A2, PEPT1

Ergometrine Oxytotic 0.25 NA 0.00018 NA -0.54 68.36 MDR1 High Low III

Ergotamine Antimigraine 1 NA 0.4 9.62 7.2 1.99 118.21 MDR1 High High I

MDR1, MRP1, OAT2,

Erythromycin Antibacterial 500 NA 0.08 13.08 8.14 0.72 193.91 High High I
OATP1A2

Ethambutol Anti-tuberculosis 400 NA 0.0016 9.6 -3.23 64.52 NA High Low III

Ethosuximide Antiepileptic 250 NA 0.042 9.7 0.38 46.17 NA High High I

Etoposide Anticancer 100 2 9.95 1.96 161 BCRP, MDR1-3,6,7, Low High II
 Partition coefficients and molecular surface properties as predictors of drug absorption 88

Table 1 (Cont)
Solubility Permeability BCS classification

pKa
Maximum Log Transporters Solubility Permeability BCS
Drug Therapeutic class Do1 Do2 Do3 PSA
dose (mg) HA BH+ D6.0 interaction class class Class

Fluoxetine Antipsychotic 20 NA 0.002 10.05 NA 21.3 MDR1 High High I

Flutamide Anticancer 250 NA 0.42 13.12 NA 74.9 NA High High I

MRP2, OAT1, OAT3,

Furosemide Diuretic 40 NA 0.02 3.04 0.26 131.01 High High I
OAT4, OCTN2

Gemfibrozil Antihyperlipidemia 300 NA 0.12 4.75 2.14 46.5 NA High High I

BSEP, MDR1, MRP1,

Glibenclamide Antidiabetic 5 NA 1 NA 2.75 121.98 High High I
OATP2B1

Griseofulvin Antifungal 500 NA 2985.07 NA 3.53 71.06 NA Low High II

Haloperidol Antipsychotic 5 NA 0.006 13.9 8.25 0.82 40.54 MDR1 High High I

Hydralazine Antihypertensive 25 NA 0.08 NA 0.56 63.83 NA High High I

Hydrochlorthiazide Diuretic 50 NA 0.48 8.95 -0.07 135.12 NA High High I

MDR1, MRP1, MRP3,

Ibuprofen NSAID 600 NA 1.17 4.41 2.12 37.3 Low High II
OAT1-4

Imipramine Antipsychotic 25 5.5 9.49 1.85 6.5 MDR1, OCT2, OCT3 Low High II

MDR1, MRP1, MRP2,

Indinavir Antiretroviral 400 NA 53.3 5.73 2.76 118.03 Low High II
OATP1A2, OATP1B1

MDR1, MRP1-8,
Indomethacin NSAID 25 6.25 4.17 0.3 68.5 Low High II
OAT1-4

Isoniazid Anti-tuberculosis 300 NA 0.01 11.27 3.79 -0.89 68.01 NA High Low III

Isosorbide dinitrate Antianginal 10 NA 4.82E-05 NA -1.75 58.92 NA High Low III

Labetalol Antihypertensive 200 NA 0.04 7.91 9.2 -0.42 95.6 NA High High I

Lamivudine (3tc) Antiretroviral 150 NA 0.17 13.83 4.41 -0.71 113.45 BCRP, MRP1 High Low III

Levamisole Anthelmintic 40 NA 0.0067 8.81 -0.15 40.9 NA High High I

Levodopa Antiparkinsonism 250 NA 0.09 2.24 9.3 -0.27 103.78 NA High High I

Lisinopril Antihypertensive 20 NA 0.02 2.18 10.51 -1.32 133 MDR1, PEPT1 High Low III

Losartan Antihypertensive 25 NA 0.49 4.24 3.1 0.89 92.5 MDR1, OAT1 High High I

Mebendazole Anthelmintic 100 NA 20 10.29 5.02 2.77 84.08 MDR1 Low High II

Mercaptopurine Anticancer 50 0.03 8.46 2.4 0.37 85.2 MRP4, MRP5 High High I

Metformin Antidiabetic 500 NA 0.002 13.1 -4.31 88.99 OCT1, OCT2 High Low III

Methionine Antidote 250 NA 0.04 2.23 9.26 -2.13 88.6 OCTN2 High Low III

BCRP, MDR1, MRP1-

Methotrexate Anticancer 10 NA 6.20E-05 3.54 5.09 NA 211 7, OAT1-4, OATP1B1, High Low III
OATP1B3, OATP1C1

Methyldopa Antihypertensive 500 NA 0.3 2.28 9.3 -2.37 103.78 PEPT1 High Low III

Metoclopramide Antiemetic 10 NA 0.0002 13.28 9.62 -7.8 67.59 NA High Low III
 Shawahna et al / DARU 2011 19 (2) 83-99 89

Table 1 (Cont)
Solubility Permeability BCS classification

pKa
Maximum Log Transporters Solubility Permeability BCS
Drug Therapeutic class Do1 Do2 Do3 PSA
dose (mg) HA BH+ D6.0 interaction class class Class

Metronidazole Anti-Amoebic 400 NA 0.2 2.58 -1.01 78.94 NA High Low III

Morphine Analgesic 30 NA 0.0005 9.72 8.14 -1.77 52.93 MDR1 High Low III

Nalidixic acid Antibacterial 500 NA 0.73 1.2 5.95 0.33 70.5 NA High High I

BCRP, MDR1,
Nelfinavir Antiretroviral 250 NA 291.54 9.58 7.53 5.44 127.2 Low High II
OATP1A2, OATP1B1

Neostigmine Antidote 15 NA 0.00019 NA -3.03 29.54 MDR1 High Low III

Nevirapine Antiretroviral 200 NA 1.37 10.93 4.74 1.84 58.12 NA Low High II

Niclosamide Anthelmintic 500 NA 1801.8 NA 5.4 95.15 NA Low High II

Nitrofurantoin Antibacterial 100 NA 0.28 7.69 1.2 -0.41 120.73 NA High High I

Nitroglycerin Antianginal 6.4 0.02 NA 2.22 165 NA High High I

Nystatin Antifungal 200 NA 26.6 NA -0.42 319.61 NA Low High II

Omeprazole Antiulcer 20 NA 0.004 9.08 4.61 2.15 96.3 BCRP, MDR1, MRP3 High High I

Paracetamol Analgesic 500 NA 0.19 9.86 0.34 49.33 NA High High I

Penicillamine Antidote 250 NA 0.096 2.13 11.54 -1.57 102.12 NA High Low III

Phenobarbital Antiepileptic 30 NA 0.18 7.88 1.66 75.27 NA High High I

Phenoxymethylpenicillin Antibacterial 500 NA 0.02 2.62 -1.47 121.24 NA High Low III

Phenytoin Antiepileptic 100 NA 4 8.33 2.52 58.2 MDR1, MRP2 Low High II

Prazosin Antihypertensive 2 NA 0.016 6.47 -1.25 107 BCRP, MDR1, OCT1-3 High Low III

Prednisolone Antiallergic 5 NA 0.15 12.47 1.49 94.83 MDR1 High High I

Primaquine Antimalarial 7.5 NA 0.00015 10.38 -0.41 60.17 NA High High I

MDR1, OATP1A2,
Procainamide Antiarrythmic 250 NA 0.017 9.86 -1.43 58.4 High Low III
OCT1-3, OCTN1,2

Procarbazine Anticancer 50 NA 0.0006 7.46 0.11 53.2 NA High High I

Prochlorperazine Antipsychotic 5 1.34 7.82 2.42 35 NA Low High II

Procyclidine Antiparkinsonism 5 NA 2.03 10.48 0.84 23.5 NA Low High II

Promethazine Antiallergic 25 NA 0.04 8.98 2.04 31.78 MDR1 High High I

Propranolol Antihypertensive 160 NA 0.01 13.84 9.14 0.28 41.49 MDR1, NTCP, OCT2 High High I

Propylthiouracil Anticancer 100 NA 0.2 7.63 0.54 1.36 73.22 NA High High I

Pyrantel Anthelmintic 250 NA 0.012 10.97 -0.49 43.84 NA High Low III

Pyrazinamide Anti-tuberculosis 500 NA 0.09 13.91 -0.37 68.87 NA High High I

Pyridostigmine Muscle relaxant 60 NA 0.0005 NA -4.31 29.54 NA High Low III

 Partition coefficients and molecular surface properties as predictors of drug absorption 90

Table 1 (Cont)
Solubility Permeability BCS classification

pKa
Maximum Log Transporters Solubility Permeability BCS
Drug Therapeutic class Do1 Do2 Do3 PSA
dose (mg) HA BH+ D6.0 interaction class class Class

BSEP, MDR1, OAT3,

Quinidine Antiarrythmic 200 5.7 13.05 9.13 1.35 45.6 OATP1A2, OATP1B1, Low High II
OCT1,2, OCTN1,2

MDR1, OATP1A2,
Quinine Antimalarial 200 NA 0.03 13.05 9.13 0.54 45.59 OATP1C1, OCT1,2, High High I
OCTN1,2

Risperidone Antipsychotic 3 NA 0.017 7.91 1.01 61.9 NA High High I

MDR1, MRP1,2,5,
Rifampicin Anti-tuberculosis 600 NA 1.71 NA -1.75 217 OATP1A2, OATP1B1, Low Low IV
OATP1B3, OATP2B1

BCRP, MDR1,
Ritonavir Antiretroviral 100 NA 1063.8 11.47 3.48 5.28 202.26 MRP1,2, OATP1A2, Low High II
OATP1B1

Salbutamol Antiasthmatic 4 NA 0.000016 9.83 9.22 -2.84 72.72 NA High Low III

BCRP, MDR1,2,
Saquinavir Antiretroviral 200 NA 16 NA 2.84 166.75 Low High II
OATP1A2, OATP1B1

Selegiline Antiparkinsonism 5 NA 0.78 7.53 1.42 3.2 MDR1 High High I

Spironolactone Diuretic 100 NA 44.3 NA 3.12 85.74 MDR1 Low High II

Stavudine (D4T) Antiretroviral 40 NA 0.009 9.57 -0.86 78.87 NA High Low III

Sulphasalazine Antibacterial 500 NA 0.29 2.88 1.86 0.35 149.69 NA High High I

Tamoxifen Anticancer 20 NA 479.04 8.69 6.2 12.5 BCRP, BSEP, MDR1 Low High II

Theophylline Antiasthmatic 270 NA 0.25 8.6 1.05 -0.18 69.3 NA High High I

Thioacetazone Anti-tuberculosis 50 NA 0.2 NA NA 112 NA High Low III

Thioguanine
Anticancer 40 NA 0.004 7.44 3.09 -0.4 111 MRP4 High High I
(6 thioguanine)

Tinidazole Antifungal 500 NA 0.0004 NA -0.27 106 NA High High I

Trifluperazine Antipsychotic 5 NA 1.63 7.82 4.04 35 NA Low High II

Trimethoprim Antibacterial 300 NA 0.17 7.34 -0.42 105.51 MDR1 High High I

Valproic acid Antiepileptic 300 NA 0.005 4.82 -1.65 100.27 OAT3, OCTN2 High Low III

BCRP, BSEP, MDR1,

Verapamil Antihypertensive 240 NA 0.85 9.03 2.91 64 MRP1-4,7, OATP1A2, High High I
OCT1, OCTN1,2, PGP

Warfarin Anti-coagulant 5 NA 0.01 4.5 1.91 63.6 NA High High I

Zalcitabine (DDC) Antiretroviral 0.75 NA 4.96E-07 4.47 -1.51 88.2 NA High Low III

Zidovudine (zDV) Antiretroviral 100 NA 0.1 NA -0.53 91.23 PEPT1 High Low III

1- Do (dose number) calculated from solubility data taken from ref. (9); 2 Do (dose number) calculated from solubility data taken from ref. (10); 3 Do (dose number)
calculated from predicted solubility data, ACD/Labs; * The maximal dose strength on the list of national essential medicines of Pakistan; pKa values were taken from ref.
12; Calculated log D6.0 values at pH 6 using ACD/Labs; PSA calculated from ACD/Labs; Transporter interaction taken from ref. 25;BCRP: Breast cancer resistance
protein; BSEP: Bile salt export pump; MDR: Multidrug transporter; MRP: Multidrug resistance protein; NA: not available; OAT: Organic anion transporter; OATP:
Organic anion-transporting polypeptide; OCTN: Organic cation transporter; OST: Organic solute transporter; PEPT: Peptide transporter; Pgp: P-glycoprotein.
 Shawahna et al / DARU 2011 19 (2) 83-99 91

Supplementary table 1: Solubility data correlation: ACD/Labs, experimental water solubility DrugBank, ALOGPS and reliable
experimental solubility.

Solubility Solubility Solubility Reliable experimental

Drug Dose (mg) Do1 D2 D3
Class 1 Class 2 Class 3 solubility

Abacavir 300 2.9268293 0.0155844 0.99173554 Low High High High

Acetylsalicylic Acid 500 0.002 0.4347826 1.36986301 High High Low High

Aciclovir 200 2.1052632 0.4938272 0.08810573 Low High High High

Allopurinol 100 0.0101807 0.7029877 0.06802721 High High High High

Amiloride 5 0.1666667 0.01639344 High High High

Atenolol 100 0.0004 0.0296296 0.93240093 High High High High

Captopril 25 0.0001 0.02212389 High High High

Carbamazepine 200 10 45.19774 5.26315789 Low Low Low Low

Chloramphenicol 250 4.3478261 0.4 2.1691974 Low High Low High

Chloroquine 150 0.0220345 56.603774 34.2857143 High Low Low High

Cimetidine 200 0.0722022 0.16 0.98039216 High High High High

Cloxacillin 1000 0.2805049 287.76978 75.1879699 High Low Low High

Codeine 30 0.0022822 0.0133333 0.20797227 High High High High

Colchicine 0.5 0.0285714 4.44E-05 0.07246377 High High High High

Cyclophosphamide 25 0.0011682 0.002 0.00662252 High High High High

Dapsone 100 1.1428571 1.0526316 1.4084507 Low Low Low Low

Diazepam 5 1 0.4 1.63934426 High High Low High

Digoxin 0.625 0.0054348 0.01968504 High High High

Doxycycline 100 0.5405405 0.6349206 0.7751938 High High High High

Ergotamine 1 0.4 0.01793722 High High High

Fluconazole 50 0.7407407 200 0.14388489 High Low High High

Furosemide 40 0.0230548 26.666667 1.3559322 High Low Low Low

Griseofulvin 250 1492.5373 115.74074 19.8412698 Low Low Low Low

Hydralazine 50 0.1724138 0.07575758 High High High

Hydrochlorothiazide 25 0.2439024 0.1428571 0.04464286 High High High High

Ibuprofen 400 0.7804878 32.653061 23.3918129 High Low Low Low

Indinavir 400 53.333333 106.66667 33.1950207 Low Low Low Low

Levodopa 250 0.0942507 23.562677 0.3030303 High Low High High

Levonorgestrel 0.75 0.4207574 1.4705882 0.51457976 High Low High High

Levothyroxine 0.1 0.0997506 0.0038095 0.04454343 High High High High

Metformin 500 0.002 0.88888889 High High High

Methyldopa 250 0.149925 1 0.44247788 High High High High

Metronidazole 500 0.2816901 84.459459 0.008 High Low High High

Nelfinavir 250 291.54519 523.560209 Low Low Low

Nifedipine 10 1.3333333 2.25988701 Low Low Low

Nitrofurantoin 100 0.2857143 5.0327126 0.96385542 High Low High Low

Paracetamol 500 0.1966568 0.1428571 0.48192771 High High High High

Penicillamine 250 0.0968054 0.009009 0.21505376 High High High High

Penicillin V 250 0.0125723 1 2.20264317 High High Low High

Phenobarbital 100 0.625 0.3603604 1.44927536 High High Low High

Phenytoin 100 4 12.5 5.62587904 Low Low Low Low

Prednisolone 5 0.1538462 0.0896861 0.08368201 High High High High

Primaquine 15 0.0003165 1.06382979 High Low High

 Partition coefficients and molecular surface properties as predictors of drug absorption 92

Supplementary table 1 (Cont)

Solubility Solubility Solubility Reliable experimental

Drug Dose (mg) D1 D2 D3
Class 1 Class 2 Class 3 solubility

Promethazine 25 0.0478469 4.08163265 High Low High

Propranolol 40 0.0029602 2.2857143 2.01511335 High Low Low High

Propylthiouracil 50 0.1149425 0.1666667 0.42918455 High High High High

Pyrazinamide 400 0.0759734 0.1066667 0.01707577 High High High High

Pyridostigmine 60 0.0005417 0.23076923 High High High

Riboflavin 5 0.0001868 0.2361275 0.0304414 High High High High

Ritonavir 100 1063.8298 317.460317 Low Low Low

Salbutamol 4 0.000016 5.3333333 0.00744186 High Low High High

Saquinavir 200 16 323.88664 Low Low Low

Stavudine 40 0.0091376 0.016 0.00395062 High High High High

Sulfamethoxazole 400 1.509434 2.6229508 3.48583878 Low Low High Low

Theophylline 300 0.2836879 0.24 0.05240175 High High High High

Thiamine 50 0.0009126 0.0004 13.0718954 High High Low High

Trimethoprim 200 0.1152738 0.0661157 1.30081301 High High Low Low

Valproic Acid 500 0.0091258 0.004 130.718954 High High Low Low

Zidovudine 300 0.3243243 0.024 0.07361963 High High High High

1-Do (dose number) calculated from predicted solubility data, ACD/Labs; 2 Do (dose number) calculated from solubility data obtained from DrugBank
database; 3 Do (dose number) calculated from predicted solubility data, ALOGPS; Reliable experimental solubility, were taken from ref. 13.

Supplementary table 2: Solubility and permeability classification comparing the list of national essential medicines (NEML) of Pakistan
and classification of the WHOs essential medicines model list (EML)

WHO WHO NEML

NEML WHO NEML
Drug Dose Comment Permeability Permeability Comment
Dose (mg) Solubility class Solubility class
(mg) class class

Classified as low
permeability
drug based on
reliable data*;
Acetylsalicylic acid 500 300 High High High Low log D6.0 indicated
low permeability,
whereas, PSA was
lower than that of
labetalol

Aciclovir 200 200 High Low Low Low

Albendazole 400 200 Low Low inconclusive High

Classified as low
permeability
drug based on
reliable data*;
Allopurinol 100 300 High High High Low log D6.0 indicated
low permeability,
whereas, PSA was
lower than that of
labetalol

Amiloride 5 5 High High High High

Amitriptyline 25 50 High High High High

 Shawahna et al / DARU 2011 19 (2) 83-99 93

Supplementary table 2 (Cont)

WHO WHO NEML

NEML WHO NEML
Drug Dose Comment Permeability Permeability Comment
Dose (mg) Solubility class Solubility class
(mg) class class

Amlodipine 5 5 High High High High

Classified as high
classified as high permeability based
solubility based on incomplete
Amoxicillin 500 500 High Low High Low
on incomplete data*; both log D6.0
data* and PSA indicated
low permeability

Atenolol 100 100 High High Low Low

Carbamazepine 200 200 Low Low High High

NEML dose is
Cefixime 400 100 Low High lower than that inconclusive Low
of WHO

Classified as low
permeability based
Chloramphenicol 250 250 High Low Low High on reliable data*;
PSA can indicate
low permeability

Chloroquine 150 150 High High High High

Chlorphenamine 4 4 High High inconclusive High

Chlorpromazine 100 100 High High inconclusive High

Ciprofloxacin 250 250 High High inconclusive Low

Clomipramine 25 25 High High inconclusive High

Cloxacillin 1000 250 High High Low Low

NEML dose is
Dapsone 100 50 Low High lower than that High High
of WHO

NEML dose is
Diazepam 5 10 High Low higher than that High High
of WHO

Didanosine 400 400 High High Low Low

Digoxin 0.25 0.25 High High High High

Diloxanide 500 500 Low Low inconclusive High

Classified as low
permeability drug
based on reliable
Doxycycline 100 100 High High High Low data*; both log
D6.0 and PSA
indicated low
permeability

Efavirenz 200 50 Low Low inconclusive High

Both log D6.0 and

Enalapril 2.5 10 High High Low High PSA indicated
high permeability
 Partition coefficients and molecular surface properties as predictors of drug absorption 94

Supplementary table 2 (Cont)

WHO WHO NEML

NEML WHO NEML
Drug Dose Comment Permeability Permeability Comment
Dose (mg) Solubility class Solubility class
(mg) class class

Classified as low
classified as low permeability based
solubility based on incomplete
Erythromycin 250 500 Low High Low High
on incomplete data*; PSA can
data* indicate low
permeability

Ethambutol 400 400 High High Low Low

Furosemide 40 40 Low High inconclusive High

classified as low
solubility based
Glibenclamide 5 5 Low High inconclusive High
on inconclusive
data*

Griseofulvin 250 500 Low Low High High

Haloperidol 2 5 inconclusive High Low High

Classified as low
permeability drug
based on reliable
Hydralazine 50 25 High High Low High data*; both log
D6.0 and PSA
indicated high
permeability

Classified as low
permeability drug
based on reliable
Hydrochlorothiazide 25 50 High High Low High
data*; PSA can
indicate low
permeability

Ibuprofen 400 600 Low Low High High

Indinavir sulfate 400 400 Low Low inconclusive High

Isoniazid 300 300 High High inconclusive Low

Isosorbide dinitrate 5 10 High High inconclusive Low

Both log D6.0 and

Lamivudine 150 150 High High High Low PSA indicated low
permeability

Levamisole 150 40 High High inconclusive High

Levodopa 250 250 High High High High

Carbidopa 25 25 High High inconclusive Low

Mebendazole 500 100 Low Low inconclusive High

Classified as high
permeability based
on incomplete
Dl-methionine 250 250 High High High Low
data*; PSA can
indicate high
permeability

Metformin 500 500 High High Low Low

Methyldopa 250 500 High High Low Low

 Shawahna et al / DARU 2011 19 (2) 83-99 95

Supplementary table 2 (Cont)

WHO WHO NEML

NEML WHO NEML
Drug Dose Comment Permeability Permeability Comment
Dose (mg) Solubility class Solubility class
(mg) class class

Metoclopramide 10 10 High High Low Low

Classified as high
permeability drug
based on reliable
Metronidazole 500 400 High High High Low
data*; PSA can
indicate low
permeability

Morphine 10 30 High High inconclusive Low

Nelfinavir 250 250 inconclusive Low inconclusive High

Neostigmine 15 15 High High Low Low

Nevirapine 200 200 Low Low High High

Niclosamide 500 500 Low Low inconclusive High

Nitrofurantoin 100 100 Low High High High

Nystatin 200 200 inconclusive Low inconclusive High

Paracetamol 500 500 High High High High

Penicillamine 250 250 High High Low Low

Phenobarbital 100 30 High High High High

Classified as high
permeability drug
based on reliable
Penicillin v 250 500 High High High Low data*; both log
D6.0 and PSA
indicated low
permeability

Phenytoin 100 100 Low Low High High

Prednisolone 25 5 High High High High

Primaquine 15 7.5 High High High High

Promethazine 25 25 High High High High

Propranolol 40 160 High High High High

Propylthiouracil 50 100 High High High High

classified as low
solubility based
Pyrantel 250 250 Low High inconclusive Low
on inconclusive
data*

Pyrazinamide 400 500 High High inconclusive High

Quinine 300 200 High High High High

Classified as high
permeability based
on incomplete
Rifampicin 300 600 Low Low High Low
data*; both log D6.0
and PSA indicated
low permeability

Ritonavir 100 100 Low Low inconclusive High

Salbutamol 4 4 High High High Low

Saquinavir 200 200 Low Low inconclusive High

Spironolactone 25 100 inconclusive Low inconclusive High

 Partition coefficients and molecular surface properties as predictors of drug absorption 96

Supplementary table 2 (Cont)

WHO WHO NEML

NEML WHO NEML
Drug Dose Comment Permeability Permeability Comment
Dose (mg) Solubility class Solubility class
(mg) class class

PSA can indicate

Stavudine (d4t) 40 40 High High High Low
high permeability

classified as low Inconclusive

solubility based data*; PSA can
Sulphasalazine 500 500 Low High Low High
on inconclusive indicate low
data* permeability

Trimethoprim 200 300 Low High High High

Classified as high
permeability drug
based on reliable
Valproic acid 500 300 High High High Low data*; both log
D6.0 and PSA
indicated low
permeability

classified as low
solubility based
Verapamil 80 240 Low High High High
on inconclusive
data*

Warfarin 5 5 High High High High

Classified as high
permeability drug
based on reliable
Zidovudine (zdv) 300 100 High High High Low
data*; PSA can
indicate high
permeability

* Ref. (13); Ref. (16)

Supplementary table 3: Comparison of Permeability prediction based on log P, log D6.0 and PSA, by using metoprolol or labetalol as
internal standard.
Internal standard: Metoprolol Internal standard: Labetalol
Reliable
Drug Log P Log D6.0 PSA Log P cutoff Log D6.0 PSA cutoff Log P cutoff Log D6.0 PSA cutoff experimental
1.35 cutoff -1.48 65 2.31 cutoff -0.42 95.6 solubility

Abacavir 0.72 0.03 96.95 Low Low Low Low High Low Low

Acetylsalicylic Acid 1.19 -1.24 63.6 Low Low High Low Low High Low

Aciclovir -1.76 -1.76 109.83 Low Low Low Low Low Low Low

Allopurinol -1.33 -3.81 74.69 Low Low Low Low Low High Low

Amiloride 1.08 1.07 156.79 Low Low Low Low High Low High

Atenolol 0.1 -2.73 84.58 Low Low Low Low Low High Low

Captopril 0.27 -2.02 96.41 Low Low Low Low Low Low Low

Carbamazepine 2.67 2.67 46.33 High High High High High High High

Chloramphenicol 1.02 1.02 115.38 Low Low Low Low High Low Low

Chloroquine 4.69 1.2 28.16 High Low High High High High High

Cimetidine 0.26 -1.14 114.19 Low Low Low Low Low Low Low

Cloxacillin 2.53 -0.81 138.04 High Low Low High Low Low Low

Codeine 1.2 -0.99 41.93 Low Low High Low Low High Low

Colchicine 0.92 0.92 83.09 Low Low Low Low High High Low

Cyclophosphamide 0.23 0.23 51.38 Low Low High Low High High High
 Shawahna et al / DARU 2011 19 (2) 83-99 97

Supplementary table 3 (Cont)

Internal standard: Metoprolol Internal standard: Labetalol
Reliable
Drug Log P Log D6.0 PSA Log P cutoff Log D6.0 PSA cutoff Log P cutoff Log D6.0 PSA cutoff experimental
1.35 cutoff -1.48 65 2.31 cutoff -0.42 95.6 solubility

Dapsone 0.94 0.94 94.56 Low Low Low Low High High High

Diazepam 2.96 2.96 32.67 High High High High High High High

Digoxin 0.85 0.85 203.06 Low Low Low Low High Low High

Doxycycline -0.54 -3.06 181.62 Low Low Low Low Low Low High

Ergotamine 3.58 1.99 118.21 High High Low High High Low Low

Fluconazole 0.5 0.5 71.79 Low Low Low Low High High High

Furosemide 3 0.26 131.01 High Low Low High High Low Low

Griseofulvin 3.53 3.53 71.06 High High Low High High High High

Hydralazine 1 0.56 63.83 Low Low High Low High High Low

Hydrochlorothiazide -0.07 -0.07 135.12 Low Low Low Low High Low Low

Ibuprofen 3.72 2.12 37.3 High High High High High High High

Indinavir 2.88 2.76 118.03 High High Low High High Low Low

Levodopa -0.22 -0.27 103.78 Low Low Low Low High Low High

Levonorgestrel 3.92 3.92 37.3 High High High High High High High

Levothyroxine 5.93 3.38 92.78 High High Low Low High High Low

Metformin -2.31 -4.31 88.99 Low Low Low Low Low High Low

Methyldopa 0.12 -2.37 103.78 Low Low Low Low Low Low Low

Metronidazole -1.01 -1.01 78.94 Low Low Low Low Low High High

Nelfinavir 6.98 5.44 127.2 High High Low Low High Low Low

Nifedipine 2.97 2.96 110.45 High High Low High High Low High

Nitrofurantoin -0.4 -0.41 120.73 Low Low Low Low High Low High

Paracetamol 0.34 0.34 49.33 Low Low High Low High High Low

Penicillamine 0.93 -1.57 102.12 Low Low Low Low Low Low Low

Penicillin V 1.88 -1.47 121.24 High Low Low Low Low Low High

Phenobarbital 1.67 1.66 75.27 High High Low Low High High High

Phenytoin 2.52 2.52 58.2 High High High High High High High

Prednisolone 1.49 1.49 94.83 High High Low Low High High High

Primaquine 2.67 -0.41 60.17 High Low High High High High High

Promethazine 4.78 2.04 31.78 High High High High High High Low

Propranolol 3.1 0.28 41.49 High Low High High High High High

Propylthiouracil 1.37 1.36 73.22 High Low Low Low High High Low

Pyrazinamide -0.37 -0.37 68.87 Low Low Low Low High High High

Pyridostigmine -4.31 -4.31 29.54 Low Low High Low Low High Low

Riboflavin -2.02 -3.48 155.05 Low Low Low Low Low Low High

Ritonavir 5.28 5.28 202.26 High High Low Low High Low Low

Salbutamol 0.01 -2.84 72.72 Low Low Low Low Low High High

Saquinavir 4.44 2.84 166.75 High High Low High High Low Low

Stavudine -0.86 -0.86 78.87 Low Low Low Low Low High High

Sulfamethoxazole 0.89 0.49 106.6 Low Low Low Low High Low High

Theophylline -0.17 -0.18 69.3 Low Low Low Low High High High

Thiamine -1.61 -1.65 100.27 Low Low Low Low Low Low Low

Trimethoprim 0.79 -0.42 105.51 Low Low Low Low High Low High

Valproic Acid -1.61 -1.65 100.27 Low Low Low Low Low Low High

Zidovudine -0.53 -0.53 91.23 Low Low Low Low Low High High
 Partition coefficients and molecular surface properties as predictors of drug absorption 98

Supplementary table 4: Permeability data correlation: Log D6.0 ACDLabs, PSA and experimental Caco-2 permeability coefficient
(Papp).

PSA PSA Log P Log P

Permeability Permeability
Drug Papp** Log D6.0 Prediction cutoff Prediction cutoff Prediction cutoff Prediction cutoff Prediction
class class
95.6 65 1.35 2.31

Acetylsalicylic acid 2.4 106 Low -1.24 Low c High fp High fp Low c Low c

Atenolol 5.3 107 Low -2.73 Low c High fp Low c Low c Low c

Carbamazepine 2.15 10 5
High 2.67 High c High c High c High c High c

Chlorpheniramine 1.6 105 High 0.49 High c High c High c High c High c

Cimetidine 1.37 10 6
Low -1.14 Low c Low c Low c Low c Low c

Dexamethasone 2.34 10 5
High 1.87 High c High c Low fn High c Low fn

Diazepam 3.34 105 High 2.96 High c High c High c High c High c

Digoxin 5 105
High 0.85 High c Low fn Low fn Low fn Low fn

Diltiazem 4.9 105 High 2.64 High c High c Low fn High c High c

Furosemide 3.33 10 6
Low 0.26 High fp Low c Low c High fp High fp

Griseofulvin 3.68 105 High 3.53 High c High c Low fn High c High c

Hydrochlorthiazide 5.1 10 7
Low -0.07 High fp Low c Low c Low c Low c

Ibuprofen 5.25 105 High 2.12 High c High c High c High c High c

Indomethacin 2.04 10 5
High 0.3 High c High c Low fn High c High c

Labetalol 1.5 105 Ref -0.42 High c High c Low fn High c High c

Phenytoin 2.67 10 5
High 2.52 High c High c High c High c High c

Propranolol 2.75 105 High 0.28 High c High c High c High c High c

Quinine 2.04 105 High 0.54 High c High c High c High c High c

Saquinavir 5.5 10 7
Low 2.84 High fp Low c Low c High fp High fp

Sulphasalazine 1.29 107 Low 0.35 High fp Low c Low c High fp High fp

Theophylline 4.47 10 5
High -0.18 High c High c Low fn Low fn Low fn

Verapamil 2.63 105 High 2.91 High c High c High c High c High c

Zidovudine 6.93 10 6
Low -0.53 Low c High fp Low c Low c Low c

Calculated log D values at pH 6 using ACD/Labs; ** Taken from ref. 15; taken from ref. 19;
Ref: reference; c: correct; fp: false positive; fn: false negative.

CONCLUSION Second, metoprolol was conservative permeability

Within the limitations of our investigation, the internal standard as compared to labetalol. Finally,
following conclusions can be drawn. First, log D6.0 models combining log D and PSA can have the best
showed better prediction capability than log P. permeability prediction capabilities.

REFERENCES
1. Qiu Y, Chen Y, Liu L, Zhang G. Developing solid oral dosage forms: pharmaceutical theory and practice.
USA, Elsevier Inc. 2009; 341-360.
2. Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug
classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res,
1995; 12: 413-420.
3. Cook J, Addicks W, Wu YH. Application of the biopharmaceutical classification system in clinical drug
development--an industrial view. AAPS J, 2008; 10: 306-310.
4. Polli JE. In vitro studies are sometimes better than conventional human pharmacokinetic in vivo studies in
assessing bioequivalence of immediate-release solid oral dosage forms. AAPS J, 2008; 10: 289-299.
5. Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernas H, Hussain AS, Junginger HE,
Stavchansky SA, Midha KK, Shah VP, Amidon GL. Molecular properties of WHO essential drugs and
provisional biopharmaceutical classification. Mol Pharm, 2004; 1: 85-96.
6. Palm K, Stenberg P, Luthman K, Artursson P. Polar molecular surface properties predict the intestinal
absorption of drugs in humans. Pharm Res, 1997; 14: 568-571.
7. World Health Organization (WHO). National Essential Medicines List of Pakistan, 2007 (4th Revision) at
 Shawahna et al / DARU 2011 19 (2) 83-99 99

http://apps.who.int/medicinedocs/fr/m/abstract/Js17119e/ accessed on 14/12/2010.

8. The European Agency for the Evaluation of Medicinal Products (EMA), Committee for Proprietary
Medicinal Products (CPMP). Note for Guidance on the Investigation of Bioavailability and Bioequivalence.
2010.
9. Yalkowsky S, He Y. Handbook of aqueous solubility data. Boca Raton, FL. CRC Press. 2003.
10. Drugbank database. http://www.drugbank.ca/ accessed on 14/12/2010.
11. Syracuse Research Corporation. Physical/Chemical Property Database (PHYSPROP). SRC Environmental
Science Center. Syracuse, NY. 1994.
12. Block J, Beale J. Wilson & Gisvolds Textbook of Organic Medicinal and Pharmaceutical Chemistry. MD.
Lippincott Williams and Wilkins. 2004. 948-956.
13. Lindenberg M, Kopp S, Dressman JB. Classification of orally administered drugs on the World Health
Organization Model list of Essential Medicines according to the biopharmaceutics classification system.
Eur J Pharm Biopharm, 2004; 58: 265-278.
14. Kasim NA, Whitehouse M, Ramachandran C, Bermejo M, Lennernas H, Hussain AS, Junginger HE,
Stavchansky SA, Midha KK, Shah VP, Amidon GL. Molecular properties of WHO essential drugs and
provisional biopharmaceutical classification. Mol Pharm, 2004; 1: 85-96.
15. Rinaki E, Valsami G, Macheras P. Quantitative biopharmaceutics classification system: the central role of
dose/solubility ratio. Pharm Res, 2003; 20: 1917-1925.
16. World Health Organization (WHO). Proposal to waive in vivo http://whqlibdoc.who.int/trs/WHO_TRS_
937_eng.pdf.)
17. Kelder J, Grootenhuis PD, Bayada DM, Delbressine LP, Ploemen JP. Polar molecular surface as a
dominating determinant for oral absorption and brain penetration of drugs. Pharm Res, 1999; 16: 1514-
1519.
18. Food and Drug Administration (FDA), CDER. U.S. Department of Health and Human Services Food and
Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for Industry: Waiver
of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms
Based on a Biopharmaceutics Classification System. Food and Drug Administration, Ed. Rockville, MD.
2000.
19. Valope D. Drug Permeability Studies in Regulatory Biowaiver Applications. In: Ehrhardt C, Kim K, ed.
Drug absorption studies: in situ, in vitro and in silico models. Springer NY 2008; 665-696.
20. Linnankoski J, Makela JM, Ranta VP, Urtti A, Yliperttula M. Computational prediction of oral drug
absorption based on absorption rate constants in humans. J Med Chem, 2006; 49: 3674-3681.
21. Palm K, Luthman K, Ungell AL, Strandlund G, Beigi F, Lundahl P, Artursson P. Evaluation of dynamic
polar molecular surface area as predictor of drug absorption: comparison with other computational and
experimental predictors. J Med Chem, 1998; 41: 5382-5392.
22. Winiwarter S, Bonham NM, Ax F, Hallberg A, Lennernas H, Karlen A. Correlation of human jejunal
permeability (in vivo) of drugs with experimentally and theoretically derived parameters. A multivariate
data analysis approach. J Med Chem, 1998; 41: 4939-4949.
23. Box KJ. Comer JE. Using measured pKa, LogP and solubility to investigate supersaturation and predict
BCS class. Curr Drug Metab, 2008; 9: 869-878.
24. Benet LZ, Larregieu CA. The FDA should eliminate the ambiguities in the current BCS biowaiver
guidance and make public the drugs for which BCS biowaivers have been granted. Clin Pharmacol Ther,
2010; 88: 405-407.
25. Transporter Database, TP-Search. http://www.tp-search.jp/ accessed on 14/12/2010.