Prediction of drug bioavailability in humans using immobilized artificial membrane phosphatidylcholine column chromatography and in vitro hepatic metabolic clearance

Abstract

This study reports a rapid screening method for the prediction of oral drug bioavailability in humans based on combined immobilized artificial membrane (IAM) chromatographic capacity factor (k_IAM) and in vitro stability in hepatic microsomes. The fraction of drug absorbed (F_a) in humans was predicted for a set of 15 structurally diverse commercial drugs based on k_IAM values using a mobile phase consisting of acetonitrile: Dulbecco's phosphate-buffered saline. The hepatic intrinsic clearance (CL ) was calculated from in vitro disappearance half-life, and the oral bioavailability was predicted using in vitro hepatic clearance (CL_h) and F_a. Significant correlations were observed for the relationships between predicted hepatic extraction ratios (ER_h) and actual presystemic metabolism (r = 0.854) and between predicted and observed oral bioavailabilities (r = 0.805; p < 0.01). The IAM capacity factor together with the hepatic microsomal disappearance half-life may be useful in identifying compounds with high oral absorption potential in early drug discovery processes. Copyright © 2009 John Wiley & Sons, Ltd.