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 an inhibitor of cytochrome P450 (CYP) 1A2 activity, we conducted a drug interaction study with theophylline, a known CYP1A2 substrate.


METHODS
Two-way, randomized, crossover study.


METHODS
Clinical research laboratory.


METHODS
Nineteen healthy males (16 smokers, 3 nonsmokers).


METHODS
Because the a priori expectation was no effect of olanzapine on theophylline pharmacokinetics, a parallel study using cimetidine was included as a positive control. In group 1, 12 healthy subjects received a 30-minute intravenous infusion of aminophylline 350 mg after 9 consecutive days of either olanzapine or placebo. In group 2, seven healthy subjects received a similar aminophylline infusion after 9 consecutive days of either cimetidine or placebo.


RESULTS
Concentrations of theophylline and its metabolites in serum and urine were measured for 24 and 72 hours, respectively. Plasma concentrations of olanzapine and its metabolites were measured for 24 hours after the next to last dose and 168 hours after the last olanzapine dose. Olanzapine did not affect theophylline pharmacokinetics. However, cimetidine significantly decreased theophylline clearance and the corresponding formation of its metabolites. Urinary excretion of theophylline and its metabolites was unaffected by olanzapine but was reduced significantly by cimetidine. Steady-state concentrations of olanzapine (15.3 ng/ml), 10-N-glucuronide (4.9 ng/ml), and 4'-N-desmethyl olanzapine (2.5 ng/ml) were observed after olanzapine 10 mg once/day and were unaffected by coadministration of theophylline.


CONCLUSIONS
As predicted by in vitro studies, steady-state concentrations of olanzapine and its metabolites did not affect theophylline pharmacokinetics and should not affect the pharmacokinetics of other agents metabolized by the CYP1A2 isozyme.
Macias
W L
WL
Eli Lilly and Company, Lilly Research Laboratories, and Lilly Laboratory for Clinical Research, Indianapolis, Indiana 46202, USA.
Bergstrom
R F
RF
Cerimele
B J
BJ
Kassahun
K
K
Tatum
D E
DE
Callaghan
J T
JT
D000328:Adult; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D019540:Area Under Curve; D001569:Benzodiazepines; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002927:Cimetidine / Q000494:pharmacology; D018592:Cross-Over Studies; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014527:Uric Acid / Q000031:analogs & derivatives / Q000097:blood / Q000652:urine; D014970:Xanthines / Q000097:blood / Q000652:urine
D014150:Antipsychotic Agents; D001993:Bronchodilator Agents; D004791:Enzyme Inhibitors; D014970:Xanthines; D001569:Benzodiazepines; D014527:Uric Acid; C030530:1-methyluric acid; D010890:Pirenzepine; D002927:Cimetidine; D013806:Theophylline; C031274:1,3-dimethyluric acid; D000077152:Olanzapine; C029703:3-methylxanthine