Kinetics and metabolism of nomifensine in animals.

Abstract

1 The absorption, excretion, distribution and metabolism of a new antidepressant agent, nomifensine, was examined in rats, dogs and monkeys. After oral administration of 14C-nomifensine 1 mg/kg body weight, the compound was absorbed rapidly, and as shown in rats and dogs, virtually completely. Nomifensine was predominantly found in a conjugated form in the plasma of rats, dogs and monkeys. Nomifensine was bound to serum proteins (approximately 60%) and the degree of binding was not species specific. 2 The maximum levels of total radioactivity (unchanged drug and metabolites) in the blood were 0.50 ± 0.14 μg equiv./ml (n = 5) in dogs and 0.34 ± 0.17 μg equiv./ml (n = 6) in monkeys. These leves were markedly higher than those in rats, with values of 0.034 ± 0.014 μg equiv./ml at 0.5-0.75 h and 0.048 ± 0.018 μg equiv./ml at 2-8 h after dosing (second peak; n = 19). 3 The ratio of radioactivity in organs and tissues relative to plasma was small and similar to that in blood. The highest concentrations of radioactivity were measured in the excretory organs; the lowest concentrations were found in the brain. When multiple doses of 14C-nomifensine were administered accumulation was minimal. 4 After single oral doses, the plasma levels of radioactivity were higher than those of blood. Accumulation of unconjugated nomifensine in plasma could not be demonstrated in dog, and multiple doses of the drug had no influence on the elimination of either conjugated or unconjugated nomifensine. 5 Rats excreted about 50% and dogs excreted about 70% of the compound in urine, predominantly as conjugates. The metabolites found in man were also found in monkey, these being 4'-hydroxy nomifensine, 4'-hydroxy-3'-methoxy nomifensine and 3'-hydroxy-4'-methoxy nomifensine.