Received for publication July 29, 2008.
Revised August 27, 2008.
Accepted for publication August 28, 2008.

The Combination of Chemical and Antibody Inhibitors for Superior P450 3A Inhibition in Reaction Phenotyping Studies

Abstract

P450 reaction phenotyping is used to accurately determine the contribution of different P450s to the metabolism of new chemical entities. The significance of P450s to drug disposition has led to the identification of selective chemical and antibody inhibitors for individual P450 enzymes. Despite these advances, the maximum inhibition attainable is limited by the use of inhibitor concentrations which maintain selectivity for the individual P450s. Thus, most commercially available inhibitors achieve inhibition of ~80%. Herein, the combination of chemical plus antibody inhibitors was explored to find P450 3A could be selectively and completely (>99%) inhibited by using both chemical and antibody inhibitors together.

Key words: cytochrome P450, drug-drug interactions, human CYP enzymes, in vitro-in vivo prediction