DISPOSITION OF THE NOVEL ANTICANCER AGENT VINORELBINE DITARTRATE FOLLOWING INTRAVENOUS ADMINISTRATION IN MICE, RATS AND DOGS

1. KW-2307 (vinorelbine ditartrate, CAS 71486-22-1) is a new semisynth etic antitumour vinca alkaloid. Its pharmacokinetics, distribution and excretion were investigated following intravenous administration to m ice (1.2 mg/kg), rats (0.12 and 1.2 mg/kg) and dogs (0.4 mg/kg). Dose levels are expressed as the free base. 2. Plasma concentrations of dru g-related radioactivity declined in a bi- or tri-exponential manner, i nitially rapidly and then slowly (half-life of 35 h or more). Unchange d drug concentrations declined with terminal half-lives of 35.8 h in r ats and 34.5 h in dogs: a terminal phase was not observed in mice. KW- 2307 can be characterised as a drug of high clearance (3.78, 1.73 and 1.20 l/h/kg in the mice, rats and dogs, respectively) and large volume of distribution (12.7, 41.9 and 49.6 l/kg in the mouse, rat and dog, respectively). After repeated administrations for 21 days in the rat, the accumulation ratio for unchanged drug concentrations in plasma was 1.5. 3. The extent of binding of H-3-KW-2307 in vitro to proteins in the plasma of humans, dogs, rats and mice was 89, 90, 93 and 97%, resp ectively. 4. In rats, concentrations of radioactivity in most tissues exceeded those in plasma, and at 0.5 h after administration were great est in the adrenals, thyroid, pituitary, lungs, small intestine conten ts and kidneys. The lung is a target for drug action. Concentrations o f radioactivity in the brain were lowest. In pregnant rats, placental transfer of radioactivity was low, less than 1% of the dose. Concentra tions in mammary tissue, another target for drug action, exceeded thos e in plasma. The tissue distribution profile of radioactivity in rats was similar after single and repeated administrations. 5. Radioactivit y was excreted mainly in faeces (61-73% dose in 48 h and 71-79% dose i n 168 h). Biliary excretion accounted for 42.6% dose in rats during 48 h although enterohepatic cycling was probably unimportant.