PHARMACOKINETICS OF CLOZAPINE AND ITS METABOLITES IN PSYCHIATRIC-PATIENTS - PLASMA-PROTEIN BINDING AND RENAL CLEARANCE

Aims N-Desmethylclozapine and clozapine N-oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excr etion. The aim of this study was to investigate to what extent the eli mination of these metabolites in urine contributes to the total fate o f clozapine in patients and how they are handled by the kidney. Method s From 15 psychiatric patients on continuous clozapine monotherapy, bl ood and urine samples were obtained during four 2 h intervals, and clo zapine and its metabolites were assayed in serum and urine by solid-ph ase extraction and h.p.l.c. Unbound fractions of the compounds were me asured by equilibrium dialysis. Results The following unbound fraction s in serum were found (geometric means): clozapine 5.5%, N-desmethylcl ozapine 9.7%, and clozapine N-oxide 24.6%. Renal clearance values calc ulated from unbound concentrations in serum and quantities excreted in urine were for clozapine on average 11% of the creatinine clearance, whereas those of N-desmethylclozapine and clozapine N-oxide amounted t o 300 and 640%, respectively. The clearances of unbound clozapine and N-desmethylclozapine increased with increasing urine volume and decrea sing pH. All renal clearance values exhibited large interindividual va riations. The sum of clozapine and its metabolites in urine represente d on average 14% of the dose. Conclusions Clozapine, N-desmethylclozap ine and clozapine N-oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, wh ereas the metabolites undergo net tubular secretion. Metabolic pathway s alternative or subsequent to N-demethylation and N-oxidation must ma ke major contributions to the total fate of clozapine in patients.