Possible involvement of multiple human cytochrome P450 isoforms in the liver metabolism of propofol

Previous studies of propofol (2,6-diisopropylphenol) pharmacology haveshown that this widely used anaesthetic drug is extensively cleared fromthe body by conjugation of the parent molecule or its quinol metabolite. Onthe basis of potential influence of propofol on the metabolism ofco-administered agents, many investigators have evaluated the effects ofpropofol on cytochrome P450 (CYP) activities. CYP isoforms involved inpropofol metabolism are not defined. In this study, our objective was toelucidate further the CYP isoforms responsible for the hydroxylation ofpropofol. Using microsomes from 12 different human livers, we investigatedCYP isoforms involved in propofol hydroxylase activity, using selectivechemical inhibitors of CYP isoforms, correlation with immunoquantifiedspecific CYP isoform content, immunoinhibition, and 11 functionally activehuman CYP isoforms expressed in a heterologous system (yeast and human B-lymphoblastoid cells). We found a low variability in the production of thehydroxylated metabolite of propofol, 2,6-diisopropyl-1,4-quinol. Thisactivity was mediated by CYP and followed Michaelis-Menten kinetics withapparent K(M) and Vmax values of 18 microM (95% Cl 15.1- 20.1) and 2.6 nmolmin-1 mg-1 (95% Cl 2.45-2.68) respectively. Part of the propofolhydroxylase activity was mediated by CYP2C9 in human liver, especially atlow substrate concentration. Moreover, propofol was likely to bemetabolized by additional isoforms such as CYP2A6, 2C8, 2C18, 2C19 and 1A2,especially when substrate concentrations are high. This low specificityamong CYP isoforms may contribute to the low interindividual variability(two-fold) and may contribute to the low level of metabolic druginteractions observed with propofol.