Bioanalysis and pharmacokinetics of (investigational) vinca alkaloids.

Abstract

1 6 4 Introduction Analytical methods have been developed for vinblastine and several investigational semisynthetic derivatives, using selective techniques based on highpressure liquid chromatography (HPLC). These methods were implemented in comprehensive studies of plasma pharmacokinetics, tissue distribution, excretion and metabolism in animal models. The results of these studies clearly highlight the need for such selective methods and increase our knowledge about the relation between the pharmacokineric behaviour and the pharmacodynamics of this kind of antitumour agents. The vinca alkaloids vinblastine and vincristine are two naturally occurring compounds isolated from the periwinkle plant Vinca rosea. These drugs constitute an important class of antineoplastic agents, which are now being used for over three decades in a number of palliative and, in some cases, even potentially curative multidrug regimens. In the early 1960's it was already recognized that minor changes in the molecular structure could have a great impact on the pharmacological activity of these compounds. This finding has resulted in the development of a substantial number of semisynthetic analogues with the aim of either converting non-active but abundantly present substances into active ones, or of designing new analogues with improved efficacies and/or altered antitumour spectra. Former studies had indicated that vinca alkaloids enter cells by active transport mechanisms rather than by passive diffusion. Within the cells they bind to the cytoplasmatic protein tubulin, thus interfering with the normal equilibrium that exists between tubulin monomers and structures of polymerized tubulin, the so-called microtubules. Investigations by fluorescence microscopy had shown a perceptible effect after the incubation of cells at concentrations of 5-I0 ng/ml of vinblastine, whereas a twoto fourfold increase sufficed to achieve a maximal effect (e.g. a complete dissolution of microtubules). Furthermore, results obtained by clonogenic assays had shown that the exposure duration of cells to the drug is an important determinant of the severity of the ultimate cytotoxic effect.