Effects of Repeated Smoking and Quitting Cigarettes on Plasma Concentrations of Clozapine and Its N-Desmethyl and N-Oxide Metabolites in a Japanese Patient With Schizophrenia.

Clozapine (CLZ) is used for treatment-resistant schizophrenia. However, its pharmacokinetics in Japanese patients with schizophrenia have not been well described. Smoking affects the activities of cytochrome P450 (CYP), which mainly metabolizes CLZ, and patients with schizophrenia have a higher rate of smoking than others. Hence, the effects of smoking or quitting cigarettes on CLZ pharmacokinetics have been reported. Nevertheless, there are no case reports on interactions with CLZ, particularly examining OCLZ concentrations over time during repeated periods of smoking and quitting cigarettes. In a Japanese man in his 40s, trough plasma concentrations of CLZ, N-desmethyl clozapine (NCLZ) and N-oxide clozapine (OCLZ) were measured, and their ratios and the daily dose (D) were evaluated as indicators of drug metabolism. The CLZ/D ratio ([ng/mL]/[mg/day]) decreased by a median of 58.2%, whereas both NCLZ/CLZ and OCLZ/CLZ ratios increased by medians of 64.7% and 58.6%, respectively, in the total smoking period, relative to the total quitting period. The drug concentrations and their metabolic ratios fluctuated with smoking (six cigarettes daily) on and off multiple times. These results suggest that the CYP1A2-inducing effect of smoking on CLZ metabolism can be reproducible and emphasize the need for careful attention to smoking status changes, CLZ concentration measurement and dose checking in patients with schizophrenia who have a smoking habit. Further studies are required to confirm the pharmacokinetic findings obtained from the limited data in only one patient.