Disposition of clozapine in man: lack of association with debrisoquine and S-mephenytoin hydroxylation polymorphisms.

A large interindividual variability has previously been demonstrated in the bioavailability, steady-state plasma concentrations and clearance of clozapine, an atypical neuroleptic drug. To evaluate the importance of genetic factors in the metabolism of clozapine, its disposition after a single oral dose of 10 mg was studied in 15 healthy Caucasian volunteers. Five of the subjects were poor metabolisers (PM) of debrisoquine, five were PM of S-mephenytoin, and the remaining five were extensive metabolisers (EM) of both probe drugs. There was a 10-fold interindividual variation in Cmax and a 14-fold variation in AUC(0, 24) of clozapine among the 15 subjects studied. The mean (s.d.) Cmax was 117 (81) nmol l-1 and the mean AUC(0,24) value was 890 (711) nmol l-1 h. The value of t1/2,z varied 3-fold with a mean (s.d.) of 13.3 (5.0) h. There were no significant differences in the plasma concentrations or any of the pharmacokinetic parameters of clozapine between PM and EM of debrisoquine, or between the two S-mephenytoin hydroxylation phenotypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual variability in clozapine pharmacokinetics.