Computational‐Regulatory Developments in the Prediction of Oral Drug Absorption

Abstract

Early prediction of human intestinal absorption is important in selection of potential orally administered drugs. Various computational models for prediction of the fraction of dose absorbed, Fa, have been developed. In 1989, a sigmoidal relationship between Fa and drug absorption potential was shown. Since then various physicochemical descriptors of molecules (lipophilicity, polar surface area, hydrogen bond descriptors) have been found to correlate with human intestinal absorption and various attempts in estimating Fa have been reported. Most studies rely on the presupposition that Fa is mainly dependent on drug's solubility, which drives the dissolution rate in the gastrointestinal (GI) fluids, and the rate of passive drug transport across the intestinal membrane. In the same vein, the biopharmaceutics classification system (BCS) and the relevant FDA guideline classify drugs in four categories according to their aqueous solubility and permeability. However, the biopharmaceutics drug disposition classification system (BDDCS) revealed the poor predictability of permeability estimates for Fa and the major role of transporters for GI uptake of drugs. The role of solubility in the reaction limited model of dissolution and the ubiquitous presence of supersaturated solubility-dissolution phenomena in the GI lumen, call for a more physiologically relevant consideration of GI absorption.

Metadynamics for Perspective Drug Design: Computationally Driven Synthesis of New Protein–Protein Interaction Inhibitors Targeting the EphA2 Receptor

“…Computer-aided exploration of the SAR around the N -(3α-hydroxy-5β-cholan-24-oyl)- l -β-homotryptophan nucleus of compound 16 , allowed identification of two effective EphA2 antagonists (i.e., compounds 21 and 22 ) possibly endowed with improved in vitro ADME properties according to their slightly higher polar surface area (PSA, Table ). We therefore evaluated the plasma concentrations of compounds 21 and 22 following oral administration to mice. In fact, the parent compound 16 , while endowed with a lipophilicity (i.e., the distribution coefficient in n -octanol/buffer at pH 7.4, Table ) compatible with oral absorption, barely reached detectable plasma levels (i.e., < 0.01 μM) after oral administration to mice at 30 mg/kg (Figure ).…”