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Disposition of clozapine in man: lack of association with debrisoquine and S‐mephenytoin hydroxylation polymorphisms.
Author(s) -
Dahl ML,
Llerena A,
Bondesson U,
Lindstrom L,
Bertilsson L
Publication year - 1994
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.1994.tb04242.x
Subject(s) - debrisoquine , mephenytoin , disposition , clozapine , pharmacogenetics , cyp2d6 , hydroxylation , pharmacology , medicine , chemistry , genetics , psychology , biology , cytochrome p450 , genotype , psychiatry , schizophrenia (object oriented programming) , metabolism , biochemistry , gene , social psychology , enzyme
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.