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Clozapine and Metabolite Concentrations during Treatment of Patients with Chronic Schizophrenia
Author(s) -
Guitton Claire,
Kinowski JeanMarie,
Abbar Mocrane,
Chabrand Pierre,
Bressolle Françoise
Publication year - 1999
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/00912709922008245
Subject(s) - clozapine , pharmacokinetics , bioavailability , metabolite , pharmacology , sedation , volume of distribution , medicine , schizophrenia (object oriented programming) , plasma concentration , anesthesia , psychiatry
Results presented in this article are focused on the variability in pharmacokinetics. The purpose of this study was (1) to investigate intra‐ and interindividual variabilities of pharmacokinetic parameters of clozapine and its two main metabolites in plasma after multiple oral administration in 8 chronic schizophrenic patients (Study 1) and (2) to gain more information regarding plasma concentrations of these drugs after multiple doses in a group of 25 treatment‐responsive patients (Study 2). Patients were treated with clozapine in fixed daily doses (given every 8–12 hours) between 200 and 900 mg. Plasma drug concentrations were determined by high‐performance liquid chromatography. The mean volume of distribution and the total plasma clearance of clozapine, uncorrected for bioavailability, were 7 L/kg and 40.5 L/h, respectively. The terminal elimination half‐lives averaged 10.5 hours for clozapine, 19.2 hours for norclozapine, and 8.6 hours for the N‐oxide metabolite. Significant relationships were observed between clozapine and norclozapine (or clozapine N‐oxide) plasma concentrations. Large inter‐ and intrapatient variations in pharmacokinetics were observed. Clozapine was generally well tolerated by the patients, with sedation, hypersialorrhea, and tiredness as the most common side effects encountered.