Preclinical and clinical pharmacology of vinca alkaloids

Abstract

Vinca alkaloids, including vinblastine, vincristine, vindesine and vinorelbine, are widely used antineoplastic drugs, either as single agents or in combination with other drugs. The mechanism of action of these cell cycle-dependent agents is the inhibition of tubulin polymerisation into microtubules. Numerous studies have been conducted in animals and humans, using various in vivo and in vitro models, to investigate the pharmacological behaviour of this class of antitumour drug. Studies in cellular pharmacology demonstrate that vinca alkaloids are transported by multiple mechanisms, including passive diffusion and energy- and temperature-dependent active transport systems. Moreover, active efflux of drug is involved in the P-glycoprotein-mediated multidrug resistance to vinca alkaloids. This phenomenon may be modulated, in vivo and in vitro, by calcium antagonists and calmodulin inhibitors. The clinical pharmacokinetics of vinca alkaloids after intravenous bolus injection, continuous infusion and oral administration are characterised by a large apparent total volume of distribution, high total plasma clearance and long terminal elimination half-life. Biliary excretion is the main elimination pathway, with low urinary excretion. Pharmacokinetic parameters of vinca alkaloids are time- and dose-dependent, and large inter- and intra-individual variabilities have been observed. Human hepatic P-450IIIA cytochromes are involved in the metabolism of vindesine, vinblastine and probably other vinca alkaloids. Therefore, the possibility of drug-drug interactions must be considered when coadministering drugs in combination cancer chemotherapy. Development of newer semisynthetic analogues of vinca alkaloids and conjugation of vinca alkaloids with monoclonal antibodies may result in derivatives with increased antitumour activity and less clinical toxicity.