In vivo and in vitro pharmacokinetics and metabolism of vincaalkaloids in rat. II. Vinblastine and vincristine.

Vinblastine and Vincristine pharmacokinetics, including tissue distribution, metabolism and biliary excretion, were investigated, using both "in vitro" and "in vivo" models, after i.v. injections in rats. Plasma kinetic curves were best fitted to a two-compartment open model. The average terminal half-lives of VLB and VCR were 14.3 h and 7.5 h, respectively. The systemic clearance and apparent distribution volume for VLB, respectively 1.49 l/h/kg and 11.46 l/kg, were significantly greater than those of VCR, 0.12 l/h/kg and 0.41 l/kg. VCR was found to be widely distributed in tissues after i.v. injections in rats. The highest drug accumulation site was the intestine (122.0 ng/g wet tissue at 24 h). Liver and kidneys also retained high proportions of drug (respectively, 47.0 ng/g and 44.4 ng/g at 24 h). Biliary excretion was more rapid for VCR (42.7% of total radioactivity excreted over 24 h) than VLB (28.2% of total dose over 24 h). For both molecules, the percentage of radioactivity excreted in bile over 30-48 h ranged between 40-50% of total dose. At high doses, either biliary excretion rate or cumulated excretion was reduced. High performance liquid chromatography analysis of bile samples revealed four biotransformation products for VLB and three for VCR. When incubated in freshly isolated rat hepatocytes, VLB penetrated more rapidly and intensely into the cells (more than 90% of total dose taken up over 20 min) than VCR (only about 40% accumulated), probably through a passive diffusion mechanism followed by tight cellular binding. "In vitro" metabolism patterns were similar to those found "in vivo", except for the most polar metabolites observed "in vitro". Two anti-Vinca monoclonal antibodies with different specificities were used to test VCR metabolite immunoreactivities. The results suggested that some structural modifications occurred in the catharantine moiety of the molecule but that the dimeric structure seemed to be well conserved after biotransformation.