Summary
The kinetics of distribution and elimination in rats of the antitumor drug navelbine and of two of its analogues, Na-formyl navelbine and deacetyl navelbine amide, have been studied by radioimmunoassay and compared with the kinetics obtained with vinblastine and vincristine. Fitting to two-exponential curves was used to derive pharmacokinetic parameters. Clearance was found to parallel toxicity for all drugs: it increases from 0.19 l h-1 kg-1 for vincristine to 0.41 for Na-formyl navelbine, 1.4 for vinblastine, 2.3 for navelbine, and 2.6 for deacetyl navelbine amide. Terminal half-lives were longer for the Naformyl-substituted alkaloids (around 13 h) than for the others (8–10 h). We have also studied navelbine kinetics in cancer patients entered in recent navelbine clinical trials and found that navelbine pharmacokinetics are characterized by fast and extensive distribution, high clearance (0.92±0.27 l h-1 kg-1), and a relatively long terminal half-life (31.2±4.4 h). Relationships between chemical structure, pharmacokinetic properties, and toxicity or therapeutic efficiency within the Vinca alkaloid series are discussed, together with the relevance of animal models such as the rat in the screening of new antitumor drugs.
Similar content being viewed by others
References
Boston RC, Greif PC, Berman M (1981) Conversational-SA-AM—an interactive program for kinetic analysis of biological systems. Comput Prog Biomed 13: 111
Guéritte F, Pouilhès A, Mangeney P, Andriamialisoa RZ, Langlois N, Langlois Y, Potier P (1983) Composés antitumoraux du groupe de la vinblastine: dérivés de la nor-5′ anhydrovinblastine. Eur J Med Chem Chim Ther 18: 419
Mangeney P, Andriamialisoa RZ, Lallemand JY, Langlois N, Langlois Y, Potier P (1979a) 5′-Noranhydrovinblastine. Prototype of a new class of vinblastine derivatives. Tetrahedron 35: 2175
Mangeney P, Andriamialisoa RZ, Langlois N, Langlois Y, Potier P (1979b) A new class of antitumor compounds: 5′-nor and 5′,6′-seco derivatives of vinblastine-type alkaloids. J Org Chem 44: 3765
Maral R, Bourut C, Chenu E, Mathé G (1981) Experimental in vivo cross-resistance of Vinca alkaloid drugs. Cancer Chemother Pharmacol 5: 197
Maral R, Bourut C, Chenu E, Mathé G (1984) Experimental antitumor activity of 5′-nor-anhydrovinblastine, navelbine. Cancer Lett 22: 49
Nelson RL, Dyke RW, Root MA (1980) Comparative pharmacokinetics of vindesine, vincristine and vinblastine in patients with cancer. Cancer Treat Rev 7 [Suppl]: 17
Pontarotti PA, Rahmani R, Martin M, Barbet J (1984) Monoclonal antibodies to antitumor Vinca alkaloids: thermodynamics and kinetics. Molec Immunol 22: 277
Rahmani R, Barbet J, Cano JP (1983) A 125I-radiolabelled probe for vinblastine and vindesine radioimmunoassays: applications to measurements of vindesine plasma levels in man after intravenous injections and long-term infusions. Clin Chim Acta 129: 57
Rahmani R, Martin M, Barbet J, Cano JP (1984) Radioimmunoassay and preliminary pharmacokinetic studies in rats of navelbine (5′-noranhydrovinblastine). Cancer Res 44: 5609
Ribaud P, Gouveia J, Maral R, Potier P, Jasmin C, Mathé G (1981) Phase I study of 5′-noranhydrovinblastine (navelbine, NVB). Proc Am Assoc Cancer Res 22: 368
Ribaud P, Gouveia J, Langlois Y, Dorval T, Misset JL, Machover D, Musset M, Potier P, Barbet J, Cano JP, Mathé G (1984) Phase I study of 5′-noranhydrovinblastine (navelbine, NVB). Invest New Drugs 2: 127
Root MA, Gerzon K, Dyke RW (1975) A radioimmunoassay for vinblastine and vincristine. In: Second National Meeting of the Federation of Analytical Chemistry and Spectroscopy Societies, Indianapolis, Ind, p 125
Snyder JA, McIntosh BJ (1976) Microtubules. Annu Rev Biochem 45: 699
Todd GC, Gibson WR, Morton DM (1976) Toxicology of vindesine (desacetyl vinblastine amide) in mice, rats and dogs. J Toxicol Environ Health 1: 843
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rahmani, R., Guéritte, F., Martin, M. et al. Comparative pharmacokinetics of antitumor Vinca alkaloids: intravenous bolus injections of navelbine and related alkaloids to cancer patients and rats. Cancer Chemother. Pharmacol. 16, 223–228 (1986). https://doi.org/10.1007/BF00293982
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00293982