K. Kassahun et al., DISPOSITION AND BIOTRANSFORMATION OF THE ANTIPSYCHOTIC AGENT OLANZAPINE IN HUMANS, Drug metabolism and disposition, 25(1), 1997, pp. 81-93
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.