DISPOSITION OF CLOZAPINE IN MAN - LACK OF ASSOCIATION WITH DEBRISOQUINE AND S-MEPHENYTOIN HYDROXYLATION POLYMORPHISMS

A large interindividual variability has previously been demonstrated i n the bioavailability, steady-state plasma concentrations and clearanc e of clozapine, an atypical neuroleptic drug. To evaluate the importan ce 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 debris oquine, five were PM of S-mephenytoin, and the remaining five were ext ensive metabolisers (EM) of both probe drugs. There was a 10-fold inte rindividual variation in C(max) and a 14-fold variation in AUC(0,24) o f clozapine among the 15 subjects studied. The mean (s.d.) C(max) 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 E M of debrisoquine, or between the two S-mephenytoin hydroxylation phen otypes. We conclude that neither of the major genetic polymorphisms of oxidative drug metabolism contribute to the large interindividual var iability in clozapine pharmacokinetics.