Disposition and biotransformation of the antipsychotic agent olanzapine in humans.
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 microCi of [14C]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 approximately 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 radio-activity 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-deemethyl metabolites. Other metabolites, including the N-deemethyl-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 approximately 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, approximately 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.
Kassahun
K
K
Department of Drug Metabolism, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Mattiuz
E
E
Nyhart
E
E
Obermeyer
B
B
Gillespie
T
T
Murphy
A
A
Goodwin
R M
RM
Tupper
D
D
Callaghan
J T
JT
Lemberger
L
L
D000328:Adult; D014150:Antipsychotic Agents / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D001569:Benzodiazepines; D001711:Biotransformation; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D006801:Humans; D008297:Male; D000077152:Olanzapine; D010890:Pirenzepine / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D014556:Urine / Q000737:chemistry
D014150:Antipsychotic Agents; D002250:Carbon Radioisotopes; D001569:Benzodiazepines; D010890:Pirenzepine; D000077152:Olanzapine