The metabolic fate of 11-bromo-[15-3H] vincamine in rats, dogs and humans.

Abstract

During 5d following single oral doses of 3H-11-bromovincamine to rats (10 mg/kg), dogs (10 mg/kg) and humans (0.5 mg/kg), about 21 and 66%, 28 and 56% and 64 and 21% of the dose were excreted in the urine and faeces respectively, mainly within 24 and 48h. The urinary excretion of radioactivity in humans was biphasic with half-lives of about 6 and 17h, identical to those observed for decline of plasma radioactivity. The excretion of a larger proportion of the dose in the faeces of rat and dog can be attibuted to the greater extent to which biliary excretion of drugs and/or their metabolites occurs in these species compared to man : about 60% of oral or intravenous doses (10 mg/kg) of 3H-11-bromovincamine was excreted in rat bile. At least about two-thirds of an oral dose of 11-bromovincamine was absorbed in rats and humans respectively. Mean peak plasma concentrations of durg-related radioactivity (adjusted for dose) after single oral doses to rats, dogs and humans were 0.55, 0.58 and 3.0 (μg/ml)/(mg/Kg) at 4, 2 and 1h respectively. Plasma concentrations declined with half-lives of about 10 and 34h in rats and dogs respectively and biphasically in humans with half-lives of about 6 and 17h. Provided that certain assumptions are valid, comparison of the areas under the plasma radioactivity concentration-time curves obtained after oral and intravenous doses of 3H-11-bromovincamine to the animal species indicates that oral doses were well absorbed. Concentrations of total radioactivity in rat tissues after oral doses were higher than those in plasma in only a few tissues such as the liver, kidneys and lungs. After intravenous doses, however, concentrations of radioactivity were higher in most tissues than in plasma, presumably reflecting uptake of parent drug into these tissues. Concentrations of radioactivity in brain were lower than or similar to those in plasma. In all tissues examined, drug-related radioactivity concentrations were<μg eq/g after 48h. The major radioactive component in rat urine and faecal extracts, after single oral doses, corresponded to the parent drug and accounted for a total 12.3% of the dose. The remaining radioactivity was associated with a complex mixture of components. 11-Bromovincamine was only a minor component in dog and human urine (2.8% and 1.6% of the dose respectively), while a major metabolite (11-bromovincaminic acid) in human urine (23% dose) was also detected in dog urine (4.3% dose). 11-Bromovincamine represented 2.7% and 0.4% dose in dog and human faecal extracts respectively. After single oral doses, rat plasma contained a complex mixture of metabolites whereas the major radioactive component in dog and human plasma was associated with 11-bromovincamine : also present was a component corresponding to the major urine metabolite which nad a mass spectrum consistent with that of 11-bromovincaminic acid.