title: Severe Vincristine-induced Neuropathic Pain in a CYP3A5 Nonexpressor With Reduced CYP3A4/5 Activity: Case Study.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  CYP phenotype and genotype may explain the occurrence of severe neuropathy in some patients treated with vincristine.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Marija
authors.initials: M
authors.lastname: Bosilkovska
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Kuntheavy
authors.initials: K
authors.lastname: Ing Lorenzini
authors.affiliation: Department of Pediatrics, Onco-Hematology Unit, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Chakradhara Rao S
authors.initials: CR
authors.lastname: Uppugunduri
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Jules
authors.initials: J
authors.lastname: Desmeules
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.
authors.forename: Youssef
authors.initials: Y
authors.lastname: Daali
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland. Electronic address: Monica.Escher@hcuge.ch.
authors.forename: Monica
authors.initials: M
authors.lastname: Escher
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009437:Neuralgia / Q000139:chemically induced* / Q000201:enzymology; D010147:Pain Measurement; D010641:Phenotype; D014750:Vincristine / Q000009:adverse effects*; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; C542475:CEP72 protein, human; D008869:Microtubule-Associated Proteins; D014750:Vincristine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human
keywords: CEP72; CYP; P-glycoprotein; adverse drug event; neuropathy; pharmacogenetics; phenotyping; vincristine