Involvement of human liver cytochrome P4502B6 in the metabolism of propofol

Aims To determine the cytochrome P450 (CYP) isoforms involved in the oxidat ion of propofol by human liver microsomes. Methods The rate constant calculated from the disappearance of propofol in an incubation mixture with human liver microsomes and recombinant human CYP isoforms was used as a measure of the rate of metabolism of propofol. The correlation of these rate constants with rates of metabolism of CYP isoform -selective substrates by liver microsomes, the effect of CYP isoform-select ive chemical inhibitors and monoclonal antibodies on propofol metabolism by liver microsomes, and its metabolism by recombinant human CYP isoforms wer e examined. Results The mean rate constant of propofol metabolism by liver microsomes o btained from six individuals was 4.3 (95% confidence intervals 2.7, 5.7) nm ol min(-1) mg(-1) protein. The rate constants of propofol by microsomes wer e significantly correlated with S-mephenytoin N-demethylation, a marker of CYP2B6 (r=0.93, P<0.0001). but not with the metabolic activities of other C YP isoform-selective substrates. Of the chemical inhibitors of CYP isoforms tested. orphenadrine, a CYP2B6 inhibitor, reduced the rate constant of pro pofol by liver microsomes by 38% (P<0.05). while other CYP isoform-selectiv e inhibitors had no effects. Of the recombinant CYP isoforms screened. CYP2 B6 produced the highest rate constant for propofol metabolism (197 nmol min (-1) nmol P450(-1)). An antibody against CYP2B6 inhibited the disappearance of propofol in liver microsomes by 74%,. Antibodies raised against other C YP isoforms had no effect on the metabolism of propofol. Conclusions CYP2B6 is predominantly involved in the oxidation of propofol b y human liver microsomes.