Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors

Amit K. Mitra, Mark N. Kirstein, Amit Khatri, Keith M. Skubitz, Arkadiusz Z. Dudek, Edward W. Greeno, Robert A. Kratzke, Jatinder K. Lamba

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

Abstract

Aim: The aim of this study was to evaluate the association of gemcitabine pathway SNPs with detailed pharmacokinetic measures obtained from solid tumor patients receiving gemcitabine-based therapy. Materials & methods: SNPs within nine gemcitabine pathway genes, namely CDA, CMPK, DCK, DCTD, NT5C2, NT5C3, SLC28A1, SLC28A3 and SLC29A1 were analyzed for association with gemcitabine pharmacokinetics. Results: Significant association of gemcitabine clearance with SNPs in NT5C2 was identified. Clearance of 2′,2′- difluorodeoxyuridine, a gemcitabine metabolite was significantly predicted by CDA, SLC29A1 and NT5C2 SNPs. This study reports an association of formation clearance of 2′,2′-difluoro-2′-deoxycytidine triphosphate, an active form of gemcitabine with SNPs within uptake transporters SLC28A1, SLC28A3 and SLC29A1. Conclusion: Genetic variation in gemcitabine pathway genes is associated with its pharmacokinetics and hence could influence gemcitabine response. Our study identified pharmacogenetic markers that could be further tested in larger patient cohorts and could open up opportunities to individualize therapy in solid tumor patients.

Original languageEnglish (US)
Pages (from-to)1009-1021
Number of pages13
JournalPharmacogenomics
Volume13
Issue number9
DOIs
StatePublished - Jul 2012

Keywords

  • cytidine deaminase
  • deoxycytidine kinase
  • gemcitabine
  • pharmacogenomics
  • pharmacokinetics

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