W. Heptner

1 The absorption, excretion, distribution and metabolism of a new antidepressant agent, nomifensine, was examined in rats, dogs and monkeys. After oral administration of (14)C-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 (14)C-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.

1. A radioimmunoassay (RIA) has been developed for determination of both nomifensine and total nomifensine (nomifensine + conjugated nomifensine) in serum, plasma, and urine. 2. Antibodies were prepared in rabbits by immunization with N-(8-Nomifensine) succinamic acid-bovine serum albumin. 3H-labelled drug was used as tracer. Separation of free from antibody-bound nomifensine was carried out using dextran-coated charcoal. For determination of total nomifensine, the acid-labile conjugate was split by acidification. 3. The limit of detection for nomifensine is 300 pg/ml plasma and the cross-reactivity of the metabolites is less that 1%. The influence of conjugated nomifensine on the results of nomifensine can be corrected. 4. Pharmacokinetics of nomifensine were determined in healthy volunteers after oral administration of 100 mg 14C-labelled drug. Peak levels of 14C radioactivity (2,150 ng/ml), total nomifensine (1,252 ng/ml) and nomifensine (53 ng/ml) appeared within 1.5-2 h; the half-life of elimination from plasma was 1.5-2 hours. The advantages of this routine method are high sensitivity, the requirement of small amounts of plasma, and simple handling.