DISPOSITION AND BIOTRANSFORMATION OF THE ANTIPSYCHOTIC AGENT OLANZAPINE IN HUMANS

Disposition and biotransformation of the new antipsychotic agent olanz apine (OLZ) were studied in six male healthy volunteers after a single oral dose of 12.5 mg containing 100 mu Ci of [C-14]OLZ, Biological fl uids were analyzed for total radioactivity, the parent compound (GC/MS ), and metabolites (electrospray LC/MS and LC/ MS/MS). Mean radiocarbo n recovery was similar to 87%, with 30% appearing in the feces and 57% excreted in the urine. Approximately half of the radiocarbon was excr eted within 3 days, whereas >70% of the dose was recovered within 7 da ys of dosing. Circulating radioactivity was mostly restricted to the p lasma compartment of blood. Mean peak plasma concentration of OLZ was 11 ng/ml, whereas that of radioactivity was 39 ng eq/ml. Mean plasma t erminal elimination half-lives were 27 and 59 hr, respectively, far OL Z and total radioactivity. With the help of NMR and MS data, a major m etabolite of OLZ in humans was characterized as a novel tertiary N-glu curonide in which the glucuronic acid moiety is attached to the nitrog en at position 10 of the benzodiazepine ring, Another N-glucuronide wa s detected in urine and identified as the quaternary N-linked 4'-N-glu curonide. Oxidative metabolism on the allylic methyl group resulted in 2-hydroxymethyl and 2-carboxylic acid derivatives of OLZ. The methyl piperazine moiety was also subject to oxidative attack, giving rise to the N-oxide and N-desmethyl metabolites, Other metabolites, including the N-desmethyl-2-carboxy derivative, resulted from metabolic reactio ns at both the 4' nitrogen and 2-methyl groups. The 10-N-glucuronide a nd OLZ were the two most abundant urinary components, accounting for s imilar to 13% and 7% of the dose, respectively. In fecal extracts, the only significant radioactive HPLC peaks were due to 10-N-glucuronide and OLZ representing, respectively, similar to 8% and 2% of the admini stered dose. Semiquantitative data obtained from plasma samples from s ubjects given [C-14] OLZ suggest that the main circulating metabolite is 10-N-glucuronide, Thus, OLZ was extensively metabolized in humans v ia N-glucuronidation, allylic hydroxylation, N-oxidation, N-dealkylati on and a combination thereof. The 10-N-glucuronidation pathway was the most important pathway both in terms of contribution to drug-related circulating species and as an excretory product in feces and urine.