Ciprofloxacin increases serum clozapine and N-desmethylclozapine: a study in patients with schizophrenia

Objective: A possible pharmacokinetic interaction between a CYP1A2 inhibito r, ciprofloxacin, and clozapine was studied in schizophrenia patients with stable clozapine treatment. Methods: A randomised double-blind cross-over study design with two phases was used. Seven schizophrenic inpatients volunteered to receive, in additio n to their previous drug regimen, either 250 mg ciprofloxacin or placebo tw ice daily (b.i.d.) for 7 days. The phases were separated by a 7-day wash-ou t period. Serum concentrations of clozapine and its main metabolite N-desme thylclozapine were measured during both phases before the first dose on day 1 and on days 3 and 8. Results: Ciprofloxacin increased mean serum concentration of clozapine and N-desmethylclozapine by 29% (P < 0.01) and 31% (P < 0.05), respectively. Th ere was a significant positive correlation (r = 0.90, P < 0.01) between the individual concentrations of serum ciprofloxacin and the increase in conce ntrations of clozapine plus N-desmethylclozapine. The increase in serum clo zapine concentrations correlated significantly (r = 0.89, P < 0.01) with th e ratios of N-desmethylclozapine to clozapine concentrations. Conclusion: Even a low dose of ciprofloxacin can moderately increase serum concentrations of clozapine and N-desmethylclozapine. A probable mechanism of interaction is an inhibition of CYP1A2 enzyme by ciprofloxacin. The poss ibility of clinically significant interaction should be considered, especia lly when higher doses of ciprofloxacin are used concomitantly with clozapin e.