Disposition and metabolism of olanzapine in mice, dogs, and rhesus monkeys.

Olanzapine (OLZ) is a novel antipsychotic agent with a high affinity for serotonin (5-HT2), dopamine (D1/D2/D4), muscarinic (m1-m5), adrenergic (alpha 1), and histamine (H1) receptors. The pharmacokinetics, excretion, and metabolism of OLZ were studied in CD-1 mice, beagle dogs, and rhesus monkeys after a single oral and/or intravenous dose of [14C]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 was relatively short in mice and monkeys (approximately 3 hr) and long in dogs (approximately 9 hr). In mice and dogs, radioactivity was predominantly eliminated in feces; but, in monkeys, the major route of elimination of radioactivity was urine. Dogs and monkeys excreted in urine, respectively, 38% and 55% of the dose over a 168-hr period, whereas the fraction of the dose excreted in urine of mice over the collection period (120 hr) was 32%. OLZ was subject to substantial first-pass metabolism; at the tmax, OLZ accounted for 19%, 18%, and 8% of the radioactivity, in mice, dogs, and monkeys, respectively. The ratio of AUC OLZ to 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 for approximately 10%, 4%, and 2% of the dose. Metabolites that were present in urine in lesser amounts were 7-hydroxy OLZ, N-desmethyl OLZ, and N-desmethyl-2-hydroxymethyl OLZ. In dogs, the major metabolite accounting for approximately 8% of the dose was 7-hydroxy-N-oxide OLZ. Other metabolites identified were 2-hydroxymethyl OLZ, 2-carboxy OLZ, N-oxide OLZ, 7-hydroxy OLZ, and its glucuronide and N-desmethyl OLZ. The major metabolite in monkey urine was N-desmethyl-2-carboxy OLZ, and accounted for approximately 17% of the dose. In addition, N-oxide-2-hydroxymethyl, 2-carboxyl OLZ, and 2-hydroxymethyl OLZ were identified in monkey urine. Thus, in mice and dogs, OLZ was metabolized through aromatic hydroxylation, allylic oxidation, N-dealkylation, and N-oxidation reactions. In monkeys, OLZ was biotransformed mainly through double oxidation reactions involving the allylic carbon and methyl piperazine nitrogen. Whereas the oxidative metabolic profile of OLZ in animals was similar to that of humans, animals were notable for not forming appreciable amounts of the principal human metabolite (i.e. 10-N-glucuronide OLZ).