E. Mattiuz et al., DISPOSITION AND METABOLISM OF OLANZAPINE IN MICE, DOGS, AND RHESUS-MONKEYS, Drug metabolism and disposition, 25(5), 1997, pp. 573-583
Olanzapine (OLZ) is a novel antipsychotic agent with a high affinity f
or serotonin (5-HT2), dopamine (D-1/D2D4), muscarinic (m(1)-m(5)), adr
energic (alpha(1)), and histamine (H-1) receptors. The pharmacokinetic
s, excretion, and metabolism of OLZ were studied in CD-1 mice, beagle
dogs, and rhesus monkeys after a single oral and/or intravenous dose o
f [C-14]OLZ. After oral administration, OLZ was well absorbed in dogs
(absolute bioavailability of 73%) and to the extent of at least 55% in
monkeys and 32% in mice. The terminal elimination half-life of OLZ wa
s relatively short in mice and monkeys (similar to 3 hr) and long in d
ogs (similar to 9 hr). In mice and dogs, radioactivity was predominant
ly eliminated in feces; but, in monkeys, the major route of eliminatio
n of radioactivity was urine. Dogs and monkeys excreted in urine, resp
ectively, 38% and 55% of the dose over a 168-hr period, whereas the fr
action of the dose excreted in urine of mice over the collection perio
d (120 hr) was 32%. OLZ was subject to substantial first-pass metaboli
sm; at the t(max), OLZ accounted for 19%, 18%, and 8% of the radioacti
vity, in mice, dogs, and monkeys, respectively. The ratio of AUC OLZ t
o AUC radioactivity was, respectively, 10%, 14%, and 4% in mice, dogs,
and monkeys. The principal urinary metabolites in mice were 7-hydroxy
OLZ glucuronide, 2-hydroxymethyl OLZ, and 2-carboxy OLZ accounting fo
r similar to 10%, 4%, and 2% of the dose. Metabolites that were presen
t in urine in lesser amounts were 7-hydroxy OLZ, N-desmethyl OLZ, and
N-desmethyl-2-hydroxymethyl OLZ. In dogs, the major metabolite account
ing for similar to 8% of the dose was 7-hydroxy-N-oxide OLZ. Other met
abolites identified were 2-hydroxymethyl OLZ, 2-carboxy OLZ, N-oxide O
LZ, 7-hydroxy OLZ, and its glucuronide and N-desmethyl OLZ. The major
metabolite in monkey urine was N-desmethyl-2-carboxy OLZ, and accounte
d for similar to 17% of the dose. In addition, N-oxide-2-hydroxymethyl
OLZ, N-oxide-2-carboxy OLZ, N-desmethyl-2-hydroxymethyl, 2-carboxy OL
Z, and 2-hydroxymethyl OLZ were identified in monkey urine. Thus, in m
ice and dogs, OLZ was metabolized through aromatic hydroxylation, ally
lic oxidation, N-dealkylation, and N-oxidation reactions. In monkeys,
OLZ was biotransformed mainly through double oxidation reactions invol
ving the allylic carbon and methyl piperazine nitrogen. Whereas the ox
idative metabolic profile of OLZ in animals was similar to that of hum
ans, animals were notable for not forming appreciable amounts of the p
rincipal human metabolite (i.e. 10-N-glucuronide OLZ).