Disposition and biotransformation of the antipsychotic agent olanzapine in humans

Kelem Kassahun, Edward Mattiuz, Eldon Nyhart, Boyd Obermeyer, Todd Gillespie, Anthony Murphy, R. Michael Goodwin, David Tupper, J. Thomas Callaghan, Louis Lemberger

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198 Scopus citations


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 containing 100 μCi of [14C]OLZ. Biological fluids were analyzed for total radioactivity, the parent compound (GC/MS), and metabolites (electrospray LC/MB and LC/MS/MS). Mean radiocarbon recovery was ~87%, with 30% appearing in the faces and 57% excreted in the urine. Approximately 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 concentration 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 hr, respectively, 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 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 reactions at both the 4' nitrogen and 2-methyl groups. The 10-N-glucuronide end OLZ were the two most abundant urinary components, accounting for ~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, ~8% and 2% of the administered dose. Semiquantitative 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-oxidation, 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.

Original languageEnglish (US)
Pages (from-to)81-93
Number of pages13
JournalDrug Metabolism and Disposition
Issue number1
StatePublished - Jan 1 1997
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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    Kassahun, K., Mattiuz, E., Nyhart, E., Obermeyer, B., Gillespie, T., Murphy, A., Goodwin, R. M., Tupper, D., Callaghan, J. T., & Lemberger, L. (1997). Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drug Metabolism and Disposition, 25(1), 81-93.