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Disposition and biotransformation of the antipsychotic agent olanzapine in humans

Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Kassahun, Kelem; Mattiuz, Edward; Nyhart, Eldon, Jr.; Obermeyer, Boyd; Gillespie, Todd; Murphy, Anthony; Goodwin, R. Michael; Tupper, David; Callaghan, J. Thomas; Lemberger, Louis (Department of Drug Metabolism, Lilly Research Laboratories, Eli Lilly and Company, Lilly Research Centre, Indianapolis, IN 46285, USA). Drug Metabolism and Disposition, 25(1), 81-93 (English) 1997 Williams & Wilkins. CODEN: DMDSAI. ISSN: 0090-9556. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) Disposition and biotransformation of the new antipsychotic agent olanzapine (OLZ) were studied in six male healthy volunteers after a single oral dose of 12.5 mg contg. 100 mCi of [14C]OLZ. Biol. fluids were analyzed for total radioactivity, the parent compd. (GC/MS), and metabolites (electrospray LC/MS and LC/MS/MS). Mean radiocarbon recovery was ~87%, with 30% appearing in the feces and 57% excreted in the urine. Approx.There are some reagents with their cas registry numbers 187454-81-5 and 161696-76-0 are used in this study. half of the radiocarbon was excreted within 3 days, whereas >70% of the dose was recovered within 7 days of dosing. Circulating radioactivity was mostly restricted to the plasma compartment of blood. Mean peak plasma concn. of OLZ was 11 ng/mL, whereas that of radioactivity was 39 ng eq/mL. Mean plasma terminal elimination half-lives were 27 and 59 h, resp., for OLZ and total radioactivity. With the help of NMR and MS data, a major metabolite of OLZ in humans was characterized as a novel tertiary N-glucuronide in which the glucuronic acid moiety is attached to the nitrogen at position 10 of the benzodiazepine ring. Another N-glucuronide was detected in urine and identified as the quaternary N-linked 4'-N-glucuronide. Oxidative metab. on the allylic Me group resulted in 2-hydroxymethyl and 2-carboxylic acid derivs. of OLZ. The Me 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 deriv., resulted from metabolic reactions at both the 4' nitrogen and 2-Me groups. The 10-N-glucuronide and OLZ were the two most abundant urinary components, accounting for ~13% and 7% of the dose, resp. In fecal exts., the only significant radioactive HPLC peaks were due to 10-N-glucuronide and OLZ representing, resp., ~8% and 2% of the administered dose. Semiquant. data obtained from plasma samples from subjects given [14C]OLZ suggest that the main circulating metabolite is 10-N-glucuronide. Thus, OLZ was extensively metabolized in humans via N-glucuronidation, allylic hydroxylation, N-oxidn., N-dealkylation 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. .