Representation of the genes involved in the metabolism, transport, and downstream effects of the vinca alkaloid vincristine.
The anti-mitotic vinca alkaloids vinblastine, vincristine, vindesine and vinorelbine are widely used both as single agents and in combination with other antitumour drugs in cancer chemotherapy (8137344). The two complex indole alkaloids, vinblastine and vincrestine, were originally isolated from the plant Catharanthus roseus (L.) G. Don (2085431). Although both are structurally almost identical, they differ markedly in the type of tumors that they affect and in their toxic properties. Vindesine and vinorelbine are semisynthetic compounds (412968; 17442684).
The number of studies investigating the clinical pharmacokinetics of vinca alkaloids is lower than for other anticancer drugs, probably due to the analytical difficulties caused by the low doses administered. Vinca alkaloids are characterized by a large total distribution volume, rapid total plasma clearance and a long terminal half-life (8137344). In humans the main elimination route of vinca alkaloids is via faecal excretion. Vinca alkaloid pharmacokinetics are time- and dose-dependent and show large inter- and intraindividual variability (8137344; 8452560; 19588521).
To date, the identification of only two major metabolites (desacetylvinblastine and desacetylvinorelbine) in human biological fluids have been published (17442684). However, these metabolites have not been found in in-vitro experiments investigating the biotransformation of their parent drugs (17442684). A pharmacokinetics study using a radioimmunoassay found that vinblastine is metabolized to deacetylvinblastine and that this compound is more biologically active than the parent drug. No other biologically active metabolites appeared to be present in urine or in stool (889590). Vinorelbine is metabolized to its active metabolite, 4-O-deacetyl vinorelbine and two other minor metabolites, 20'-hydroxyvinorelbine and vinorelbine 6'-oxide (17306947; 11554404). In-vitro data in human hepatic microsomes indicated that CYP3A4 is the main enzyme involved in the hepatic metabolism of vinorelbine (16176333; 10950859).
The involvement of human cytochrome CYP3A isozymes in vindesine metabolism was demonstrated and the drug was converted into one major metabolite upon incubation with human liver microsomes (8452560). Other vinca alkaloids (vinblastine, vincristine and vinorelbine) exerted an inhibitory effect on vindesine biotransformation, indicating a possible involvement of the CYP3A subfamily in their metabolism (8452560).
In-vitro data showed that CYP3A4 and CYP3A5 were the only CYPs resulting in a substantial loss of the parent drug vincristine and formation of the major metabolite M1 and two minor metabolites, M2 and M4 (16679390). CYP3A5 was more efficient in catalyzing the formation of M1 compared with CYP3A4 (16679390). The hepatic clearances of vincristine were 5-fold higher for CYP3A5 high expressers than low expressers using a bank of human liver microsomes phenotyped for CYP3A4 and CYP3A5 expression (17272675). This result and similar investigations indicate that polymorphic expression of CYP3A5 may be a determinant in the CYP-mediated clearance of vincristine (17272675; 18650247).
ABCB1 is implicated in the resistance and pharmacokinetics of vinca alkaloids. ABCB1 mediates the biliary excretion of vinblastine and vincristine on the apical side of hepatocytes (17442684). ABCC1 transport of vincristine requires glutathione (9281595; 9823323). ABCB1, ABCC1, ABCC2, ABCC3, ABCC10, RALBP1 have been reported in association with vincristine resistance (16620787; 19118001; 17143522).
To circumvent the problem of vinca alkaloid resistance, vinflunine, a synthetic vinca alkaloid, has been developed (19192956). Vinflunine has shown superior preclinical antitumor activity, and displays a different pattern of resistance, compared with other agents in the vinca alkaloid class (18538175).
In-vitro studies suggest that ABCB1 polymorphisms at the 1236, 2677, and/or 3435 positions significantly minimize protein functionality (16883550). Additionally, the G571A (G191R) variant reduced, in-vitro, the degree of ABCB1-mediated resistance on vincristine by approximately 5-fold (18723777). Only a few clinical studies have tested the hypothesis that genetic variations in ABCB1 gene may contribute to inter-patient variation in vincristine pharmacokinetics, treatment response and toxicity. When SNPs of the ABCB1 gene were retrospectively analyzed in children with acute lymphoblastic leukemia treated with vincristine, no association was found between the SNPs C3435T or G2677T and vincristine pharmacokinetics or toxicity (15371983; 12851703). A recent study suggests that focusing on haplotype analysis rather than individual polymorphisms to determine the effects of ABCB1 SNPs in terms of drug response and clinical outcome may be helpful (18408561).
The most frequent and clinically important side-effect of vincristine is neurotoxicity (10226730). Non-neural side effects are markedly less common but can include alopecia and myelosuppression (10226730). Drugs know to potentiate vincristine-induced neurotoxicity through inhibition of CYP3A enzymes or inhibition of ABCB1, include nifedipine, cyclosporine, itraconazole, and voriconazole (19588521). Carbamazepine and phenytoin as CYP3A inducers increase the clearance of vincristine (10613614).
Vinca alkaloids inhibit cell proliferation by binding to microtubules, which leads to a mitotic block and apoptosis (15057285). Vincristine and related compounds induce destabilization of microtubules by binding to tubulin and blocking the polymerization (15579115). Exposure of cells to vinca alkaloids results in an induction of tumor protein p53 and cyclin-dependent kinase inhibitor 1A (p21) and in rapid alterations of protein kinase activities (10501907). These protein kinases are directly or indirectly responsible for BCL-2 phosphorylation, which results in the inactivation of BCL-2 function (7753834). The induction of BCL-2 phosphorylation is followed by the loss of its ability to form heterodimers with BAX. The loss of BCL-2 function together with the elevations of p53 and p21 lead to apoptosis (10501907).
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Entities in the Pathway
Drugs/Drug Classes (1)
Relationships in the Pathway
|Arrow From||Arrow To||Controllers||PMID|
|vincristine||metabolite M1||CYP3A4, CYP3A5||16679390, 17272675, 18650247|
|vincristine||metabolite M2||CYP3A4, CYP3A5||16679390, 17272675, 18650247|
|vincristine||metabolite M4||CYP3A4, CYP3A5||16679390, 17272675, 18650247|
|BCL2||BAX-BCL2 (BAX, BCL2)||BCL2||7753834|
|vincristine||vincristine||ABCB1, ABCC1, ABCC10, ABCC2, ABCC3, RALBP1||12851703, 15371983, 16620787, 16883550, 17143522, 18408561, 18723777, 19118001|
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