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

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Abstract
During 5 days following single oral doses of 3H-11-bromovincamine [an antihypertensive] 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 feces, respectively, mainly within 24 and 48 h. The urinary excretion of radioactivity in humans was biphasic with half-lives of about 6 and 17 h, identical to those observed for decline of plasma radioactivity. The excretion of a larger proportion of the dose in the feces of rat and dog can be attributed 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 i.v. doses (10 mg/kg) of 3H-11-bromovincamine were excreted in rat bile. At least about 2/3 of an oral dose of 11-bromovincamine was absorbed in rats and humans, respectively. Mean peak plasma concentrations of drug-related radioactivity (adjusted for dose) after single oral doses to rats, dogs and humans were 0.55, 0.58 and 3.0 (.mu.g/ml)/(mg/kg) at 4, 2 and 1 h, respectively. Plasma concentrations declined with half-lives of about 10 and 34 h in rats and dogs, respectively, and biphasically in humans with half-lives of about 6 and 17 h. Provided that certain assumptions are valid, comparison of the areas under the plasma radioactivity concentration-time curves obtained after oral and i.v. doses of 3H-11-bromovincamine to the animal species indicates that oral doses are 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 i.v. doses, 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 < 1 .mu.g eq/g after 48 h. The major radioactive component in rat urine and fecal extracts, after single oral doses, corresponded to the parent drug and accounted for a total of 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 fecal 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 had a mass spectrum consistent with that of 11-bromovincaminic acid.