Severe Vincristine-induced Neuropathic Pain in a CYP3A5 Nonexpressor With Reduced CYP3A4/5 Activity: Case Study

Clin Ther. 2016 Jan 1;38(1):216-20. doi: 10.1016/j.clinthera.2015.10.017. Epub 2015 Nov 10.

Abstract

Purpose: Peripheral neuropathy is a frequent vincristine-induced adverse effect. Vincristine is a substrate of P-glycoprotein and is metabolized by the cytochrome P-450 (CYP) 3A5 and 3A4 isoforms, with CYP3A5 contributing to 75% of the intrinsic clearance of vincristine. Alterations in the function of these proteins may lead to an increase in vincristine toxicity. CYP3A5 nonexpressor status has been associated with vincristine-induced peripheral neuropathy. The severity of neuropathy has been reported to be inversely correlated to vincristine metabolite concentrations. Recently, the presence of a mutation in the CEP72 gene, which encodes for a protein involved in microtubule formation, has also been associated with vincristine-induced peripheral neuropathy. However, a clear correlation between genetic polymorphisms and vincristine toxicity has not been established.

Methods: Here we report the case of a 21-year old patient in whom severe neuropathic pain developed after vincristine treatment.

Findings: The patient was a CYP3A5 nonexpressor and presented with reduced CYP3A4/5 functional activity, a likely reason for the occurrence of the adverse event, as genotyping showed that his status was wild type for the ABCB1 and CEP72 genes.

Implications: CYP phenotype and genotype may explain the occurrence of severe neuropathy in some patients treated with vincristine.

Keywords: CEP72; CYP; P-glycoprotein; adverse drug event; neuropathy; pharmacogenetics; phenotyping; vincristine.

Publication types

  • Case Reports

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Antineoplastic Agents, Phytogenic / adverse effects*
  • Cytochrome P-450 CYP3A / metabolism*
  • Genotype
  • Humans
  • Male
  • Microtubule-Associated Proteins / genetics
  • Neuralgia / chemically induced*
  • Neuralgia / enzymology
  • Pain Measurement
  • Phenotype
  • Vincristine / adverse effects*
  • Young Adult

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Antineoplastic Agents, Phytogenic
  • CEP72 protein, human
  • Microtubule-Associated Proteins
  • Vincristine
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human