title: Pathway-based pharmacogenomics of gemcitabine pharmacokinetics in patients with solid tumors.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors: Department of Experimental & Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.
authors: Amit K
authors: AK
authors: Mitra
authors: Mark N
authors: MN
authors: Kirstein
authors: Amit
authors: A
authors: Khatri
authors: Keith M
authors: KM
authors: Skubitz
authors: Arkadiusz Z
authors: AZ
authors: Dudek
authors: Edward W
authors: EW
authors: Greeno
authors: Robert A
authors: RA
authors: Kratzke
authors: Jatinder K
authors: JK
authors: Lamba
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D003564:Cytidine Deaminase / Q000235:genetics*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003842:Deoxycytidine Kinase / Q000235:genetics; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics*; D005260:Female; D005467:Floxuridine / Q000031:analogs & derivatives / Q000378:metabolism; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; C438649:SLC29A1 protein, human; D005467:Floxuridine; D003841:Deoxycytidine; D003842:Deoxycytidine Kinase; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human; D003564:Cytidine Deaminase; C084565:2',2'-difluoro-2'-deoxyuridine; D000093542:Gemcitabine