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

Abstract

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 M 1 , M 4 , and M 5 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 M 5 R, indicate their potential to trigger activation of nausea-associated receptors during chemotherapy with VLB. It has been shown that metabolite 20-hydroxy-VLB (metabolite 10) demonstrates a stronger binding affinity to the vinca site of tubulin than VLB; however, they have similar modes of action. VLB and metabolite 10 have similar gastric solubility (FaSSGF), intestinal solubility (FeSSIF), and log P values. Metabolite 10 has a more acceptable pharmacokinetic profile than VLB, a better gastric and intestinal solubility. Furthermore, metabolite 10 was found to be less bound to plasma proteins than VLB. These are desired and essential features for effective drug bioavailability. Metabolite 10 is not a substrate of CYP2D6 and thus is less likely to cause drug–drug interactions and ADRs compared to its parent drug. The hydroxyl group added upon metabolism of VLB suggests that it can also be a reasonable starting compound for designing the next generation of antimitotic drugs to overcome P-glycoprotein-mediated multidrug resistance, which is often observed with vinca alkaloids.

From Proteomic Mapping to Invasion-Metastasis-Cascade Systemic Biomarkering and Targeted Drugging of Mutant BRAF-Dependent Human Cutaneous Melanomagenesis

“…Since WM266-4 cells have been subjected to a structural MT network re-modeling during the IMC process ( Figure 5 ), vinblastine ( Vinca alkaloid), a specific MT-destabilizing agent [ 317 , 318 , 319 , 320 , 321 ], was subsequently analyzed for its capacity to kill melanoma cells ( Figure 9 ). Interestingly, WM266-4 presented a significant tolerance to vinblastine exposure for 24 h compared to WM115 at all administered doses, with the higher ones (50 and 100 μM) exhibiting the most important and clinically relevant differences ( Figure 9 B), which could be beneficially exploited for advanced disease therapeutic management.…”

Investigation of Protective Effects of Quercetin on Oxidative Stress Induced by Vinblastine in Bone Marrow of Rats

“…Finally one of the side effects of chemotherapy agents is dehydration and our results are in line with the other studies. 38 Treatment with quercetin could improve water intake that could be mentioned for ameliorating chemotherapy side effects.…”

Green Nanotechnology of MGF-AuNPs for Immunomodulatory Intervention in Prostate Cancer Therapy

“…The superior antiangiogenic features of vinblastine restrain the tumor growth while decelerating malignant angiogenesis in vast majority of human cancers. 77,78 Therefore, we have compared the antiangiogenic characteristics of MGF-AuNPs with the FDA approved vinblastine. Our results, as depicted in Figure 10C, compellingly infer that the anti-angiogenesis effects of MGF-AuNPs are comparable with the FDA approved drug vinblastine.…”