Comparative pharmacokinetics of antitumor Vinca alkaloids: intravenous bolus injections of navelbine and related alkaloids to cancer patients and rats.

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 1 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 Na-formyl-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 1 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.