Purely in silico BCS classification: science based quality standards for the world's drugs.

BCS classification is a vital tool in the development of both generic and innovative drug products. The purpose of this work was to provisionally classify the world's top selling oral drugs according to the BCS, using in silico methods. Three different in silico methods were examined: the well-established group contribution (CLogP) and atom contribution (ALogP) methods, and a new method based solely on the molecular formula and element contribution (KLogP). Metoprolol was used as the benchmark for the low/high permeability class boundary. Solubility was estimated in silico using a thermodynamic equation that relies on the partition coefficient and melting point. The validity of each method was affirmed by comparison to reference data and literature. We then used each method to provisionally classify the orally administered, IR drug products found in the WHO Model list of Essential Medicines, and the top-selling oral drug products in the United States (US), Great Britain (GB), Spain (ES), Israel (IL), Japan (JP), and South Korea (KR). A combined list of 363 drugs was compiled from the various lists, and 257 drugs were classified using the different in silico permeability methods and literature solubility data, as well as BDDCS classification. Lastly, we calculated the solubility values for 185 drugs from the combined set using in silico approach. Permeability classification with the different in silico methods was correct for 69-72.4% of the 29 reference drugs with known human jejunal permeability, and for 84.6-92.9% of the 14 FDA reference drugs in the set. The correlations (r(2)) between experimental log P values of 154 drugs and their CLogP, ALogP and KLogP were 0.97, 0.82 and 0.71, respectively. The different in silico permeability methods produced comparable results: 30-34% of the US, GB, ES and IL top selling drugs were class 1, 27-36.4% were class 2, 22-25.5% were class 3, and 5.46-14% were class 4 drugs, while ∼8% could not be classified. The WHO list included significantly less class 1 and more class 3 drugs in comparison to the countries' lists, probably due to differences in commonly used drugs in developing vs industrial countries. BDDCS classified more drugs as class 1 compared to in silico BCS, likely due to the more lax benchmark for metabolism (70%), in comparison to the strict permeability benchmark (metoprolol). For 185 out of the 363 drugs, in silico solubility values were calculated, and successfully matched the literature solubility data. In conclusion, relatively simple in silico methods can be used to estimate both permeability and solubility. While CLogP produced the best correlation to experimental values, even KLogP, the most simplified in silico method that is based on molecular formula with no knowledge of molecular structure, produced comparable BCS classification to the sophisticated methods. This KLogP, when combined with a mean melting point and estimated dose, can be used to provisionally classify potential drugs from just molecular formula, even before synthesis. 49-59% of the world's top-selling drugs are highly soluble (class 1 and class 3), and are therefore candidates for waivers of in vivo bioequivalence studies. For these drugs, the replacement of expensive human studies with affordable in vitro dissolution tests would ensure their bioequivalence, and encourage the development and availability of generic drug products in both industrial and developing countries.

Lack of interaction between the peptidomimetic substrates captopril and cephradine.

Intestinal peptide transporters, including hPEPT1, facilitate the absorption of cephalosporins and angiotensin-converting enzyme inhibitors, and have been investigated as a means to improve oral drug absorption. Renal peptide transporters including hPEPT2, may also facilitate renal reabsorption of such compounds. In vitro and animal studies suggest that co-administration of peptidomimetic compounds may alter oral pharmacokinetics, although this has not been well studied in humans. The purpose of this study was to determine whether co-administration of the hPEPT substrates captopril and cephradine alters the oral pharmacokinetics of either agent. Nine healthy male volunteers received a single oral 25-mg dose of captopril, a single oral 500-mg dose of cephradine, or concurrent ingestion of captopril and cephradine in a cross-over manner. Venous blood samples were taken and captopril and cephradine pharmacokinetics were determined using noncompartmental analyses. No significant differences were observed in captopril or cephradine pharmacokinetics when administered together as compared to each agent alone (a marginal decrease in C(max) was observed for both captopril and cephradine during co-administration [5-15%]; however, differences were not statistically significant). The results of our study suggest that hPEPT1 and hPEPT2 are unlikely to contribute to clinically important drug interactions in humans.

Enhanced absorption and growth inhibition with amino acid monoester prodrugs of floxuridine by targeting hPEPT1 transporters.

A series of amino acid monoester prodrugs of floxuridine was synthesized and evaluated for the improvement of oral bioavailability and the feasibility of target drug delivery via oligopeptide transporters. All floxuridine 5'-amino acid monoester prodrugs exhibited PEPT1 affinity, with inhibition coefficients of Gly-Sar uptake (IC50) ranging from 0.7 - 2.3 mM in Caco-2 and 2.0 - 4.8 mM in AsPC-1 cells, while that of floxuridine was 7.3 mM and 6.3 mM, respectively. Caco-2 membrane permeabilities of floxuridine prodrugs (1.01 - 5.31 x 10(-6 )cm/sec) and floxuridine (0.48 x 10(-6 )cm/sec) were much higher than that of 5-FU (0.038 x 10(-6) cm/sec). MDCK cells stably transfected with the human oligopeptide transporter PEPT1 (MDCK/hPEPT1) exhibited enhanced cell growth inhibition in the presence of the prodrugs. This prodrug strategy offers great potential, not only for increased drug absorption but also for improved tumor selectivity and drug efficacy.

A provisional biopharmaceutical classification of the top 200 oral drug products in the United States, Great Britain, Spain, and Japan.

Orally administered, immediate-release (IR) drug products in the top 200 drug product lists from the United States (US), Great Britain (GB), Spain (ES), and Japan (JP) were provisionally classified based on the Biopharmaceutics Classification System (BCS). The provisional classification is based on the aqueous solubility of the drugs reported in readily available reference literature and a correlation of human intestinal membrane permeability for a set of 29 reference drugs with their calculated partition coefficients. Oral IR drug products constituted more that 50% of the top 200 drug products on all four lists, and ranged from 102 to 113 in number. Drugs with dose numbers less than or equal to unity are defined as high-solubility drugs. More than 50% of the oral IR drug products on each list were determined to be high-solubility drugs (55-59%). The provisional classification of permeability is based on correlations of the human intestinal permeabilities of 29 reference drugs with the calculated Log P or CLogP lipophilicity values for the uncharged chemical form. The Log P and CLogP estimates were linearly correlated (r2 = 0.79) for 187 drugs. Metoprolol was chosen as the reference compound for permeability and Log P or CLogP. A total of 62-69.0% and 56-60% of the drugs on the four lists exhibited CLogP and Log P estimates, respectively, greater than or equal to the corresponding metoprolol value and are provisionally classified as high-permeability drugs. We have compared the BCS classification in this study with the recently proposed BDDCS classification based on fraction dose metabolism. Although the two approaches are based on different in vivo processes, fraction dose metabolized and fraction dose absorbed are highly correlated and, while depending on the choice of reference drug for permeability classification, e.g., metoprolol vs cimetidine or atenolol, show excellent agreement in drug classification. In summary, more than 55% of the drug products were classified as high-solubility (Class 1 and Class 3) drugs in the four lists, suggesting that in vivo bioequivalence (BE) may be assured with a less expensive and more easily implemented in vitro dissolution test.

Dissolution and solubility behavior of fenofibrate in sodium lauryl sulfate solutions.

The solubility of fenofibrate in pH 6.8 McIlvaine buffers containing varying concentrations of sodium lauryl sulfate was determined. The dissolution behavior of fenofibrate was also examined in the same solutions with rotating disk experiments. It was observed that the enhancement in intrinsic dissolution rate was approximately 500-fold and the enhancement in solubility was approximately 2000-fold in a pH 6.8 buffer containing 2% (w/v) sodium lauryl sulfate compared to that in buffer alone. The micellar solubilization equilibrium coefficient (k*) was estimated from the solubility data and found to be 30884+/-213 L/mol. The diffusivity for the free solute, 7.15x10(-6) cm2/s, was calculated using Schroeder's additive molal volume estimates and Hayduk-Laurie correlation. The diffusivity of the drug-loaded micelle, estimated from the experimental solubility and dissolution data and the calculated value for free solute diffusivity, was 0.86x10(-6) cm2/s. Thus, the much lower enhancement in dissolution of fenofibrate compared to its enhancement in solubility in surfactant solutions appears to be consistent with the contribution to the total transport due to enhanced micellar solubilization as well as a large decrease (approximately 8-fold) in the diffusivity of the drug-loaded micelle.

Molecular properties of WHO essential drugs and provisional biopharmaceutical classification.

The purpose of this study is to provisionally classify, based on the Biopharmaceutics Classification System (BCS), drugs in immediate-release dosage forms that appear on the World Health Organization (WHO) Essential Drug List. The classification in this report is based on the aqueous solubility of the drugs reported in commonly available reference literature and a correlation of human intestinal membrane permeability for a set of 29 reference drugs with their calculated partition coefficients. The WHO Essential Drug List consists of a total of 325 medicines and 260 drugs, of which 123 are oral drugs in immediate-release (IR) products. Drugs with dose numbers less than or equal to unity [Do = (maximum dose strength/250 mL)/solubility < or = 1] are defined as high-solubility drugs. Drug solubility for the uncharged, lowest-solubility form reported in the Merck Index or USP was used. Of the 123 WHO oral drugs in immediate-release dosage forms, 67% (82) were determined to be high-solubility drugs. The classification of permeability is based on correlations of human intestinal permeability of 29 reference drugs with the estimated log P or CLogP lipophilicity values. Metoprolol was chosen as the reference compound for permeability and log P or CLogP. Log P and CLogP were linearly correlated (r2 = 0.78) for 104 drugs. A total of 53 (43.1%) and 62 (50.4%) drugs on the WHO list exhibited log P and CLogP estimates, respectively, that were greater than or equal to the corresponding metoprolol value and are classified as high-permeability drugs. The percentages of the drugs in immediate-release dosage forms that were classified as BCS Class 1, Class 2, Class 3, and Class 4 drugs using dose number and log Pwere as follows: 23.6% in Class 1, 17.1% in Class 2, 31.7% in Class 3, and 10.6% in Class 4. The remaining 17.1% of the drugs could not be classified because of the inability to calculate log P values because of missing fragments. The corresponding percentages in the various BCS classes with dose number and CLogP criteria were similar: 28.5% in Class 1, 19.5% in Class 2, 35.0% in Class 3, and 9.8% in Class 4. The remaining 7.3% of the drugs could not be classified since CLogP could not be calculated. These results suggest that a satisfactory bioequivalence (BE) test for more than 55% of the high-solubility Class 1 and Class 3 drug products on the WHO Essential Drug List may be based on an in vitro dissolution test. The use of more easily implemented, routinely monitored, and reliable in vitro dissolution tests can ensure the clinical performance of drug products that appear on the WHO Essential Medicines List.

Gene expression in the human intestine and correlation with oral valacyclovir pharmacokinetic parameters.

The transport of valacyclovir, the l-valyl ester of acyclovir, has been suggested to be mediated by several carrier-mediated pathways in cell culture and animal models. The role and importance of these transporters in modulating valacyclovir absorption in humans has not been determined, however. Recent advances in genomic technology have facilitated the rapid and simultaneous determination of global mRNA expression profiles for thousands of genes in tissue biopsies directly associated with the absorption process, thereby dramatically increasing the value of studies in humans. In this article, we describe correlations of pharmacokinetic parameters following oral valacyclovir or acyclovir administration with expression levels of intestinal genes in humans. Highly positive and significant correlations were observed with 4F2hc, an activator of cation-preferring amino acid transport systems, and human oligopeptide transporter (HPT1), an oligopeptide transporter expressed at higher levels in the human intestine compared with oligopeptide transporter (PEPT1). The validation of HPT1 microarray data with reverse transcription-polymerase chain reaction and the enhanced valacyclovir uptake in HeLa/HPT1 cells suggest that the role of HPT1 in transport of peptides and peptidomimetics drugs needs to be examined in more detail. The interrelation of 4F2hc and HPT1 in transport may be of interest. No significant correlations of valacyclovir pharmacokinetic parameters with PEPT1 and with organic cation or anion transporter expression levels were observed. The highly negative correlations observed with known efflux pumps such as MDR1 (P-glycoprotein) and MRP2 (cMOAT), as well as with the CYP450 IIIA subfamily may indicate that these proteins may regulate the cellular accumulation and metabolism of acyclovir.

Variability in cimetidine absorption and plasma double peaks following oral administration in the fasted state in humans: correlation with antral gastric motility.

The role of gastrointestinal motility and pH in determining cimetidine bioavailability as well as double peaks in plasma profiles following oral administration, in the quiescent or active phase of antral motility, to humans in the fasted state was examined. Plasma cimetidine-time curves did not show the presence of double peaks in any subject following intravenous administration. The incidence of double peaks was 73% following oral administration and was independent of antral migrating motility complex phase. Further, it was found that oral administration of cimetidine in the quiescent phase resulted in significantly higher bioavailability and in other pharmacokinetic parameters compared to that obtained following administration in the active phase. Excellent linearity in plots of motility peaks vs. plasma peaks with slopes close to unity were evident for both quiescent (r(2)=0.93) and active phase (r(2)=0.97) administration. A total of 14 peaks out of 22 (10 subjects, 64%) and 20 out of 27 peaks (11 subjects, 74%), were accounted for in quiescent and active phase oral administration, respectively. The proximal occurrence of plasma peaks to antral motility peaks typical of phase III contractions strongly implies that motility patterns may be responsible for secondary maxima following oral cimetidine administration in the fasted state.