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

摘要

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'(int)) 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.