Pharmacokinetics of clozapine and its metabolites in psychiatric patients: plasma protein binding and renal clearance.
OBJECTIVE
N-Desmethylclozapine and clozapine N-oxide are major metabolites of the atypical neuroleptic clozapine in humans and undergo renal excretion. The aim of this study was to investigate to what extent the elimination of these metabolites in urine contributes to the total fate of clozapine in patients and how they are handled by the kidney.


METHODS
From 15 psychiatric patients on continuous clozapine monotherapy, blood and urine samples were obtained during four 2 h intervals, and clozapine and its metabolites were assayed in serum and urine by solid-phase extraction and h.p.l.c. Unbound fractions of the compounds were measured by equilibrium dialysis.


RESULTS
The following unbound fractions in serum were found (geometric means): clozapine 5.5%, N-desmethylclozapine 9.7%, and clozapine N-oxide 24.6%. Renal clearance values calculated 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 to 300 and 640%, respectively. The clearances of unbound clozapine and N-desmethylclozapine increased with increasing urine volume and decreasing pH. All renal clearance values exhibited large interindividual variations. The sum of clozapine and its metabolites in urine represented on average 14% of the dose.


CONCLUSIONS
Clozapine, N-desmethylclozapine and clozapine N-oxide are highly protein-bound in serum. Clozapine is, after glomerular filtration, largely reabsorbed in the tubule, whereas the metabolites undergo net tubular secretion. Metabolic pathways alternative or subsequent to N-demethylation and N-oxidation must make major contributions to the total fate of clozapine in patients.
Schaber
G
G
Department of Toxicology, University of Tübingen, Germany.
Stevens
I
I
Gaertner
H J
HJ
Dietz
K
K
Breyer-Pfaff
U
U
D000328:Adult; D014150:Antipsychotic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism*; D003024:Clozapine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D012559:Schizophrenia / Q000378:metabolism*
D014150:Antipsychotic Agents; D001798:Blood Proteins; C058272:norclozapine; D003024:Clozapine; C079149:clozapine N-oxide