In vitro inhibition of rat and human liver microsomal enzymes by 4-hydroxycoumarin anticoagulants and related compounds

Abstract

The in vitro inhibition of rat and human liver microsomal mixed-function oxidase by 4-hydroxycoumarin, phenprocoumon, warfarin, acenocoumarin, bishydroxycoumarin, and salicylic acid is reported. Warfarin was used for detailed kinetic analysis. It caused a modified type II spectrum (420 nm maximum), with a K s value of 0.21–0.25 m M. Inhibition of aniline hydroxylation was noncompetitive, with a K i of 11.7 m M; aminopyrine demethylation was competitively inhibited, with a K i of 0.13 m M. I 50 values are reported for the other compounds studied. Warfarin inhibited aminopyrine demethylation to a similar extent in rat and human liver microsomes, whereas inhibition of aniline hydroxylation was more pronounced in hepatic microsomes from rats compared to human. The possible clinical significance of these findings is discussed.