Abstract

Excretion and metabolism of zoniporide was investigated in humans following intravenous infusion of [¹⁴C]zoniporide at 80 mg dose. Bile was the primary route of excretion since 57% of dose was recovered in the feces following IV infusion. Zoniporide was primary cleared via metabolism in humans. 2-Oxozoniporide (M1), was the major excretory and circulating metabolite in humans and was catalyzed by aldehyde oxidase (K_M 3.4 μM; V_max 74 pmol/min/mg protein). Metabolites M2 (17% of the dose) and M3 (6.4% of circulating radioactivity), in which the guanidine moiety was hydrolyzed to a carboxylic acid, were also detected in human feces and plasma respectively suggesting that hydrolysis was another route of metabolism of zoniporide in humans. The metabolism and excretion of [¹⁴C]zoniporide in rats and dogs was also evaluated. Like humans, bile was the primary route of excretion of the radiolabeled material in both the species and metabolism was the primary route of clearance. A comparison of plasma metabolites showed that for M3, rats had a higher concentration than human or dog. M1 was absent in dog and present in human and rat plasma at comparable levels, while comparison of excreta showed that the total body burden to M1 was greater in rat than in human. No further evaluation of M2 was considered since it was detected only in the human fecal extracts. Hence, no further toxicological evaluation of the three human metabolites was undertaken.