Disposition of the novel anticancer agent vinorelbine ditartrate following intravenous administration in mice, rats and dogs

Arzneimittelforschung. 1993 Dec;43(12):1367-77.

Abstract

1. KW-2307 (vinorelbine ditartrate, CAS71486-22-1) is a new semisynthetic antitumour vinca alkaloid. Its pharmacokinetics, distribution and excretion were investigated following intravenous administration to mice (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 drug-related radioactivity declined in a bi- or tri-exponential manner, initially rapidly and then slowly (half-life of 35 h or more). Unchanged drug concentrations declined with terminal half-lives of 35.8 h in rats and 34.5h 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 3H-KW-2307 in vitro to proteins in the plasma of humans, dogs, rats and mice was 89, 90, 93 and 97%, respectively. 4. In rats, concentrations of radioactivity in most tissues exceeded those in plasma, and at 0.5 h after administration were greatest in the adrenals, thyroid, pituitary, lungs, small intestine contents and kidneys. The lung is a target for drug action. Concentrations of radioactivity in the brain were lowest. In pregnant rats, placental transfer of radioactivity was low, less than 1% of the dose. Concentrations in mammary tissue, another target for drug action, exceeded those in plasma. The tissue distribution profile of radioactivity in rats was similar after single and repeated administrations. 5. Radioactivity was excreted mainly in faeces (61-73% dose in 48 h and 71-79% dose in 168 h). Biliary excretion accounted for 42.6% dose in rats during 48 h although enterohepatic cycling was probably unimportant.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacokinetics*
  • Autoradiography
  • Bile / metabolism
  • Chromatography, High Pressure Liquid
  • Dogs
  • Female
  • Half-Life
  • Injections, Intravenous
  • Male
  • Maternal-Fetal Exchange
  • Mice
  • Mice, Inbred C57BL
  • Pregnancy
  • Protein Binding
  • Rats
  • Rats, Wistar
  • Species Specificity
  • Tissue Distribution
  • Vinblastine / administration & dosage
  • Vinblastine / analogs & derivatives*
  • Vinblastine / pharmacokinetics
  • Vinorelbine

Substances

  • Antineoplastic Agents
  • Vinblastine
  • Vinorelbine