title: Inducing effect of phenobarbital on clozapine metabolism in patients with chronic schizophrenia.
abstract: The steady state plasma concentrations of clozapine and its two major metabolites, norclozapine and clozapine N-oxide, were compared in patients with schizophrenia treated with clozapine in combination with phenobarbital (n=7), and in control patients treated with clozapine alone (n=15). Patients were matched for sex, age, body weight, and antipsychotic dosage. Patients comedicated with phenobarbital had significantly lower plasma clozapine levels than those of the controls (232+/-104 versus 356+/-138 ng/ml; mean, SD, p < 0.05). Plasma norclozapine levels did not differ between the two groups (195+/-91 versus 172+/-61 ng/ml, NS), whereas clozapine N-oxide levels were significantly higher in the phenobarbital group (115+/-49 versus 53+/-31 ng/ml, p < 0.01). Norclozapine/clozapine and clozapine N-oxide/ clozapine ratios were also significantly higher (p < 0.001) in patients comedicated with phenobarbital. These findings suggest that phenobarbital stimulates the metabolism of clozapine, probably by inducing its N-oxidation and demethylation pathways.
authors.affiliation: Institute of Pharmacology, University of Messina, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Facciolà
authors.forename: A
authors.initials: A
authors.lastname: Avenoso
authors.forename: E
authors.initials: E
authors.lastname: Spina
authors.forename: E
authors.initials: E
authors.lastname: Perucca
mesh_terms: D000328:Adult; D003024:Clozapine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D004790:Enzyme Induction; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital / Q000494:pharmacology*; D012559:Schizophrenia / Q000378:metabolism*
chemical_list: C058272:norclozapine; D003577:Cytochrome P-450 Enzyme System; D003024:Clozapine; C079149:clozapine N-oxide; D010634:Phenobarbital