Multiple-dose pharmacokinetics of clozapine in patients with chronic schizophrenia

The pharmacokinetic parameters of clozapine and its two main metabolites, N -desmethylclozapine (norclozapine, active metabolite) and clozapine N-oxide , were evaluated, after oral administration, in 19 patients with chronic sc hizophrenia. Plasma and red blood cell (RBC) drug concentrations were deter mined by high-performance liquid chromatography. Large interpatient variati ons in pharmacokinetic parameters of clozapine and its two metabolites were observed. Plasma clozapine concentration peaked, on average, at 2.3 hours. The mean volume of distribution and the total plasma clearance, uncorrecte d for bioavailability, were 6 L/kg and 38 L/hr, respectively. The terminal elimination half-lives averaged 7.6 hours for clozapine, 13 hours for norcl ozapine, and 7 hours for the N-oxide metabolite. The mean RBC/plasma concen tration ratios were 23, 61, and 81% for clozapine, N-desmethylclozapine, an d clozapine N-oxide, respectively. From RBC concentration data, the mean el imination half-lives were 7.6 hours for clozapine, 16 hours for N-desmethyl clozapine, and 8 hours for the N-oxide metabolite. The average value for bl ood clearance of clozapine was 54.7 L/hr. Significant correlations were obs erved between dose and maximum plasma concentrations and between dose and a rea under the curve concentrations; these results suggested Linear steady-s tate pharmacokinetics over the range of concentrations studied.