Effects of Antiepileptic Drugs, Carbamazepine and Phenytoin, on Plasma Concentrations of Clozapine and Its N-Desmethyl and N-Oxide Metabolites in Japanese Patients With Schizophrenia.

Clozapine (CLZ) is used for treatment-resistant schizophrenia. However, in Japanese patients, its pharmacokinetics are still not well described, and there are no case reports about drug interactions between CLZ and concomitant antiepileptics that can affect cytochrome P450 (CYP) activity, because CLZ is mainly metabolized by CYP. In two Japanese cases, for therapeutic drug monitoring, the trough plasma concentrations of CLZ, N-desmethyl clozapine (NCLZ) and N-oxide clozapine (OCLZ) were measured, and the ratios of them and the daily dose (D) were used as indicators of drug metabolism. In a male patient in his 20s, the CLZ/D ratio ([ng/mL]/[mg/day]) was significantly decreased, and both NCLZ/CLZ and OCLZ/CLZ ratios were significantly increased with carbamazepine, relative to CLZ alone. In another male patient in his 30s, the CLZ/D ratio was lower with phenytoin than without phenytoin. The NCLZ/CLZ ratio was higher with phenytoin than without phenytoin. Despite these expectations, the OCLZ/CLZ ratio showed a slight decrease with phenytoin. These results in the two Japanese cases demonstrate the effects of antiepileptics on plasma concentrations, not only of CLZ but also of its major metabolites NCLZ and OCLZ. Metabolism-enhancing interactions with CLZ were demonstrated for carbamazepine, a CYP3A4- and CYP1A2-inducer. However, for phenytoin, which is also known as a CYP3A4-inducer, the drug interactions with CLZ were not very clear due to the small limited data. These pharmacokinetic findings in only two cases must be confirmed by further investigations.