Disposition and Biotransformation of the Antipsychotic Agent Olanzapine in Humans

• Published in: Drug metabolism and disposition Vol. 25; no. 1; pp. 81 - 93
• Main Authors: Kelem Kassahun, Edward Mattiuz, Eldon Nyhart, Jr, Boyd Obermeyer, Todd Gillespie, Anthony Murphy, R. Michael Goodwin, David Tupper, J. Thomas Callaghan, Louis Lemberger
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-01-1997
• Subjects: Adult; Antipsychotic Agents - blood; Antipsychotic Agents - metabolism; Antipsychotic Agents - pharmacokinetics; Benzodiazepines; Biological and medical sciences; Biotransformation; Carbon Radioisotopes; Feces - chemistry; Humans; Male; Medical sciences; Neuropharmacology; Pharmacology. Drug treatments; Pirenzepine - analogs & derivatives; Pirenzepine - blood; Pirenzepine - metabolism; Pirenzepine - pharmacokinetics; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Urine - chemistry; Human; Olanzapine; Neuroleptic; Psychotropic; Single dose; Oral administration; Normal; Pharmacokinetics
• ISSN: 0090-9556; 1521-009X

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 [ 14 C]OLZ. Biological fluids were analyzed for total radioactivity, the parent compound (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. 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 and 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 [ 14 C]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.