Absorption Classification of Oral Drugs Based on Molecular Surface Properties

Abstract

The aim of this study was to investigate whether easily calculated and comprehended molecular surface properties can predict drug solubility and permeability with sufficient accuracy to allow theoretical absorption classification of drug molecules. For this purpose, structurally diverse, orally administered model drugs were selected from the World Health Organization (WHO)'s list of essential drugs. The solubility and permeability of the drugs were determined using well-established in vitro methods in highly accurate experimental settings. Descriptors for molecular surface area were generated from low-energy conformations obtained by conformational analysis using molecular mechanics calculations. Correlations between the calculated molecular surface area descriptors, on one hand, and solubility and permeability, on the other, were established with multivariate data analysis (partial least squares projection to latent structures (PLS)) using training and test sets. The obtained models were challenged with external test sets. Both solubility and permeability of the druglike molecules could be predicted with high accuracy from the calculated molecular surface properties alone. The established correlations were used to perform a theoretical biopharmaceutical classification of the WHO-listed drugs into six classes, resulting in a correct prediction for 87% of the essential drugs. An external test set consisting of Food and Drug Administration (FDA) standard compounds for biopharmaceutical classification was predicted with 77% accuracy. We conclude that PLS models of easily comprehended molecular surface properties can be used to rapidly provide absorption profiles of druglike molecules early on in drug discovery.

Preparation, Characterization, and In Vitro Intestinal Permeability Evaluation of Thalidomide–Hydroxypropyl-β-Cyclodextrin Complexes

“…−5 cm/s, which categorizes thalidomide as a highly permeable drug (38). Our data corroborate previous reports showing that thalidomide has favorable properties for intestinal permeation, being rapidly transported through cells (39,40).…”

Decrease in Intracellular Concentration Causes the Shift in Km Value of Efflux Pump Substrates

“…Passive permeability can be measured relatively easily with parallel artificial membrane permeability assay or cell cultures (Hidalgo, 2001) or predicted from the molecular properties of the chemical (Bergström et al, 2003). Kinetic parameters of a transporter, e.g., P-glycoprotein (P-gp), may be evaluated based on binding to the protein (Döppenschmitt et al, 1999), ATP hydrolysis in microsomal preparations (Boulton et al, 2002), inhibition studies (Gao et al, 2001), or permeability experiments with suitable cell monolayers (Horie et al, 2003;Troutman and Thakker, 2003;Balakrishnan et al, 2007).…”

A Validated Stability-Indicating HPLC Assay Method for Flucytosine in Bulk Drug

“…The precision of the method was studied by determining the concentrations of the drug Flucytosin in the tablet for six times [19] .The results of the precision study (Table 3) indicate the reliability of the method (RSD %< 2). …”

“…Sample solution 500 ppm of Flucytosine in 100ml calibrated flask containing acetonitrile and water mixture (25:75.The desired concentration for the drug was obtained by accurate dilution and the analysis was followed up as in the general analytical procedure [18,19]. Selectivity Selectivity is the ability of the method to assess unequivocally the analyte in the presence of components, which may be expected to be present.…”