LACK OF EFFECT OF OLANZAPINE ON THE PHARMACOKINETICS OF A SINGLE AMINOPHYLLINE DOSE IN HEALTHY-MEN

Objective. To test whether olanzapine, an atypical antipsychotic, is a n inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate. Design . Two-way, randomized, crossover study. Setting. Clinical research lab oratory Subjects. Nineteen healthy males (16 smokers, 3 nonsmokers). I nterventions. Because the a priori expectation was no effect of olanza pine on theophylline pharmacokinetics, a parallel study using cimetidi ne was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg aft er 9 consecutive days of either olanzapine or placebo. In group 2, sev en healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo. Measurements and Mai n Results. Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma con centrations of olanzapine and its metabolites were measured for 24 hou rs after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. Howeve r, cimetidine significantly decreased theophylline clearance and the c orresponding formation of its metabolites. Urinary excretion of theoph ylline and its metabolites was unaffected by olanzapine but was reduce d significantly by cimetidine. Steady-state concentrations of olanzapi ne (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4'-N-desmethyl olan zapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and w ere unaffected by coadministration of theophylline. Conclusion. As pre dicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and s hould not affect the pharmacokinetics of other agents metabolized by t he CYP1A2 isozyme.