Metabolites of Vinca Alkaloid Vinblastine: TubulinBinding and Activation of Nausea-Associated Receptors

Vinblastine (VLB) is an antimitotic drug that binds to the vinca site of tubulin. The molecule possesses a high molecular weight and a complex chemical structure with many possibilities of metabolization. Despite advances in drug discovery research in reducing drug toxicity, the cause and mechanism of VLB-induced adverse drug reactions (ADRs) remains poorly understood. VLB is metabolized to at least 35 known metabolites, which have been identified and collected in this present work. This study also explores how VLB metabolites affect nausea-associated receptors such as muscarinic, dopaminergic, and histaminic. The metabolites have stronger binding interactions than acetylcholine (ACh) for muscarinic M1, M4, and M5 receptors and demonstrate similar binding profiles to that of the natural substrate, ACh. The affinities of VLB metabolites to dopaminergic and histaminic receptors, their absorption, distribution, metabolism, excretion, toxicity properties, and the superiority of VLB to ACh for binding to M5R, ...