Disposition of 8-methyl-8-azabicyclo[3,2,1]octan-3-yl 3,5-dichlorobenzoate, a potent 5-hydroxytryptamine antagonist, and two metabolites in dogs and monkeys.

The disposition of 8-methyl-8-azabicyclo[3,2,1]octan-3-yl 3,5-dichlorobenzoate (MDL 72,222; 1), a potent 5-hydroxytryptamine antagonist, and its N-demethylated and N-oxide metabolites was studied in dogs and monkeys. After single, intravenous doses of 1 at 5 mg/kg, the mean terminal half-lives of 1 in plasma were 2.6 h in the dog and 3.8 h in the monkey. The mean half-life of the N-demethylated metabolite in dogs (approximately 20 h) was very similar to that in monkeys. However, the mean half-life of the N-oxide metabolite in dogs (10.8 h) was different from that in monkeys (3.9 h). The steady-state volume of distribution of 1 was 16 L/kg in dogs and 8.9 L/kg in monkeys. Examination of the mean residence times revealed that 1, in both species, and the N-oxide metabolite, in dogs, distributed to the peripheral tissue, whereas the distribution of the N-demethylated metabolite in both species and the N-oxide metabolite in monkeys was limited mainly to the systemic circulation. Compound 1 was metabolized extensively in both species. In dogs, 0.7, 2.5 and 40.6% of the administered dose were excreted in 0-120-h urine samples as 1 and its N-demethylated and N-oxide metabolites, respectively. In monkeys, however, the corresponding percentages were 0.8, 0.7, and 1.8%. Most of the administered dose in monkeys was excreted in urine as 3,5-dichlorobenzoic acid and its glycine conjugate.