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 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, 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.

Figure 1

Chemical structures of (A) VLB and (B) vinorelbine.

Figure 2

Thirty-five identified metabolites of VLB.

Figure 3

Main binding interactions at the dopaminergic receptor D₂. (A) Pose views of overlaid dopamine (spheres), VLB, and metabolite 34 docked into D₂R (sticks). Binding interactions of (B) dopamine; (C) VLB; and (D) metabolite 34. Hydrogen bonds are shown in dashed lines.

Figure 4

Main binding interactions at the histaminic receptor H₁. (A) Pose view of histamine (spheres), VLB, and metabolite 22 (sticks) docked into H₁R. Binding interactions of (B) histamine; (C) VLB; and (D) metabolite 22. Hydrogen bonds are shown in dashed lines.

Figure 5

Main binding interactions at the histaminic receptor H₃. (A) Pose view of histamine (spheres), VLB, and metabolite 18 (sticks) docked into H₃R. Binding interactions of (B) histamine; (C) VLB; and (D) metabolite 18. Hydrogen bonds are shown in dashed lines.

Figure 6

Main binding interactions at the muscarinic receptor M₁. (A) Pose view of ACh (spheres), VLB, and metabolite 22 (sticks) docked into M₁R. Binding interactions of (B) ACh; (C) VLB; and (D) metabolite 22. Hydrogen bonds are shown in dashed lines.

Figure 7

Main binding interactions at the muscarinic receptor M₄. (A) Pose view of ACh (spheres), VLB, and metabolite 13 (sticks) docked into M₄R. Binding interactions of (B) ACh; (C) VLB; and (D) Metabolite 13. Hydrogen bonds are shown in dashed lines.

Figure 8

Binding interactions of VLB metabolites docked into M₄R. (A) Metabolite 19; (B) metabolite 18; (C) metabolite 34; (D) metabolite 22; (E) metabolite 23; and (F) metabolite 10. ACh is shown in white sticks and hydrogen bonds in dashed lines.

Figure 9

Main binding interactions at the muscarinic receptor M₅. (A) Pose view of ACh (spheres), VLB, and metabolite 18 (sticks) docked into M₅R. Binding interactions of (B) ACh; (C) VLB; and (D) metabolite 18. Hydrogen bonds are shown in dashed lines.

Figure 10

Binding interactions of (A) metabolite 23 and (B) metabolite 23 docked into M₅R. ACh is shown in white sticks and hydrogen bonds in dashed lines.

Figure 11

Main binding interactions at the vinca site of tubulin. (A) Structure of α- and β-tubulin coupled with docked VLB (spheres), colored in blue and green, respectively. Binding interactions of (B) VLB, (C) metabolite 10 and, (D) metabolite 19. Hydrogen bonds are shown in dashed lines.