In vivo and in vitro pharmacokinetics and metabolism of vincaalkaloids in rat. I. Vindesine (4-deacetyl-vinblastine 3-carboxyamide).

Vindesine (VDS) pharmacokinetics, including tissue distribution, metabolism and elimination, were investigated in rats using both in vivo and in vitro models. VDS was found to be intensively distributed in tissues after i.v. injection in rat. The most important drug accumulation site was the spleen (615.0 ng/g at 24 h). Liver and kidneys also retained VDS in significant amounts (respectively 170.1 +/- 11.0 ng/g and 145.0 +/- 17.0 ng/g at 24 h). Urine excretion of drug over 7 days was low (10.1 +/- 1.8% of total dose) and consisted mainly of unchanged drug (more than 85%). The major excretion route for VDS was the feces (69.6 +/- 2.5% of total dose) via the bile (50% of total dose excreted in 72 h). High performance liquid chromatography analysis (HPLC) of collected bile samples revealed the excretion of three VDS biotransformation products. These results were confirmed in vitro using freshly isolated rat hepatocytes in suspension. Rapid and high VDS uptake by liver cells, probably through a passive diffusion mechanism followed by a tight cellular binding, was demonstrated. Moreover, VDS was intensively converted, in vitro, into four metabolites which were rapidly excreted into the extracellular medium. In contrast, the intracellular medium contained almost exclusively unchanged drug, presumably fixed to tubulin proteins. Two anti-VDS monoclonal antibodies with different specificities were used to test metabolite immunoreactivities. The results suggested that some structural modifications occurred in the catharantine moiety of the molecule but that the VDS dimeric structure seemed well conserved after biotransformation.