Isolation and identification of clozapine metabolites in patient urine.
2001
Biotransformation products of the atypical neuroleptic clozapine were isolated from urine samples of three schizophrenic patients by solid-phase extraction, liquid-liquid extraction for the separation of unpolar and polar metabolites, and thin-layer chromatography followed by final purification by high-performance liquid chromatography. Their structures were elucidated by mass spectrometry and 1 H NMR spectroscopy and in some cases by enzymatic deconjugation. Besides the known metabolites desmethylclozapine, clozapine N -oxide, 8-deschloro-8-hydroxyclozapine, and 8-deschloro-8-hydroxydesmethylclozapine, the unpolar fraction contained 7-hydroxyclozapine and a compound in which the piperazine ring of clozapine was partially degraded to an ethylenediamine derivative. Novel metabolites identified in the polar fraction were the sulfate and glucuronide conjugates of 7-hydroxyclozapine N -oxide, 8-deschloro-8-hydroxyclozapine- O -glucuronide, and the O -glucuronide of N -hydroxydesmethylclozapine; further conjugates were tentatively identified as 9-hydroxydesmethylclozapine- O -sulfate and 6-hydroxyclozapine- O -sulfate. In addition, the previously described conjugates 7-hydroxydesmethylclozapine- O -sulfate, 7-hydroxyclozapine- O -glucuronide and - O -sulfate, 8-deschloro-8-hydroxydesmethylclozapine- O -glucuronide, and the quaternary ammonium glucuronide of clozapine were detected.
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