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 monkevs. After oral administration ot '4C-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 gg equiv./ml (n= 5) in dogs and 0.34 + 0.17 jg equiv./ml (n = 6) in monkeys. These leves were markedly higher than those in rats, with values of 0.034 ± 0.014 gg equiv./ml at 0.5-0.75 h and 0.048 + 0.018 jLg 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 '4C-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.

Determination of nomifensine by a sensitive radioimmunoassay.

“…Animal experiments have shown that nomifensine is absorbed almost quantitatively (Kellner et al, 1977). Metabolic studies in urine samples indicate a biotransformation to acid-labile and stable conjugates .…”

Identification of Multiple Glutathione Conjugates of 8-Amino- 2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline maleate (Nomifensine) in Liver Microsomes and Hepatocyte Preparations: Evidence of the Bioactivation of Nomifensine

“…Reports of metabolite identification in humans in vivo revealed multiple hydroxylated modification at the phenyl ring ( Fig. 1, nomifensine hydroxylated metabolites I, II, and III), suggesting that a reactive ortho-quinone (through the oxidation of catechol at the C ring) or a quinone-methide (through the oxidation of phenol at the C ring) intermediate could be formed (Kellner et al, 1977;Heptner et al, 1978;Hornke et al, 1980;Lindberg and Syvälahti, 1986;Kalgutkar and Soglia, 2005). However, no GSH adducts of nomifensine arene oxidative intermediates have been reported.…”

Metabolism of Nomifensine to a Dihydroisoquinolinium Ion Metabolite by Human Myeloperoxidase, Hemoglobin, Monoamine Oxidase A, and Cytochrome P450 Enzymes

“…Generation and sequestration of such a metabolite within tissues, such as blood cells or hepatocytes, could be a possible cause of toxicity. However, in the early reports describing the metabolism of nomifensine in vivo, no observation of a dihydroisoquinolinium ion was made (Kellner et al, 1977;Heptner et al, 1978;Hornke et al, 1980;Lindberg and Syvalahti, 1986). No reports on the metabolism of this compound using in vitro methods have been described.…”

“…In an examination of the metabolism of nomifensine in vivo, the observed metabolites included alterations of the phenyl ring, including conjugates suggesting the existence of a catechol intermediate metabolite (Kellner et al, 1977;Heptner et al, 1978;Hornke et al, 1980;Lindberg and Syvalahti, 1986). These represent two possibilities of structural elements in nomifensine that could underlie the toxicity of the drug.…”