DISPOSITION AND METABOLISM OF OLANZAPINE IN MICE, DOGS, AND RHESUS-MONKEYS

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).