title: SLC28A3 genotype and gemcitabine rate of infusion affect dFdCTP metabolite disposition in patients with solid tumours.
abstract: BACKGROUND
  Gemcitabine is used for the treatment of several solid tumours and exhibits high inter-individual pharmacokinetic variability. In this study, we explore possible predictive covariates on drug and metabolite disposition.
  
  
  METHODS
  Forty patients were enrolled. Gemcitabine and dFdU concentrations in the plasma and dFdCTP concentrations in peripheral blood mononuclear cell were measured to 72 h post infusion, and pharmacokinetic parameters were estimated by nonlinear mixed-effects modelling. Patient-specific covariates were tested in model development.
  
  
  RESULTS
  The pharmacokinetics of gemcitabine was best described by a two-compartment model with body surface area, age and NT5C2 genotype as significant covariates. The pharmacokinetics of dFdU and dFdCTP were adequately described by three-compartment models. Creatinine clearance and cytidine deaminase genotype were significant covariates for dFdU pharmacokinetics. Rate of infusion of <25 mg m(-2) min(-1) and the presence of homozygous major allele for SLC28A3 (CC genotype) were each associated with an almost two-fold increase in the formation clearance of dFdCTP.
  
  
  CONCLUSIONS
  Prolonged dFdCTP systemic exposures (≥72 h) were commonly observed. Infusion rate <25 mg m(-2) min(-1) and carriers for SLC28A3 variant were each associated with about two-fold higher dFdCTP formation clearance. The impacts of these covariates on treatment-related toxicity in more selected patient populations (that is, first-line treatment, single disease state and so on) are not yet clear.
authors.affiliation: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: A
authors.initials: A
authors.lastname: Khatri
authors.affiliation: 1] Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA [2] Clinical Pharmacology Shared Resource of Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: B W
authors.initials: BW
authors.lastname: Williams
authors.affiliation: 1] Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA [2] Clinical Pharmacology Shared Resource of Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fisher
authors.affiliation: Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: R C
authors.initials: RC
authors.lastname: Brundage
authors.affiliation: 1] Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA [2] Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA [3] Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: V J
authors.initials: VJ
authors.lastname: Gurvich
authors.affiliation: Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA.
authors.forename: L G
authors.initials: LG
authors.lastname: Lis
authors.affiliation: 1] Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA [2] Department of Medicine, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Skubitz
authors.affiliation: 1] Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA [2] Department of Medicine, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: A Z
authors.initials: AZ
authors.lastname: Dudek
authors.affiliation: 1] Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA [2] Department of Medicine, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: E W
authors.initials: EW
authors.lastname: Greeno
authors.affiliation: 1] Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA [2] Department of Medicine, School of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Kratzke
authors.affiliation: 1] Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA [2] Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA [3] PUMA-Institute of Personalized Medicine, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Lamba
authors.affiliation: 1] Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, MN 55414, USA [2] Clinical Pharmacology Shared Resource of Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55414, USA [3] Masonic Comprehensive Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA [4] PUMA-Institute of Personalized Medicine, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: M N
authors.initials: MN
authors.lastname: Kirstein
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D003564:Cytidine Deaminase / Q000235:genetics / Q000378:metabolism; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D005838:Genotype; D006801:Humans; D007262:Infusions, Intravenous; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D026901:Membrane Transport Proteins; C065171:cif nucleoside transporter; D003841:Deoxycytidine; D015720:5'-Nucleotidase; C508048:NT5C2 protein, human; D003564:Cytidine Deaminase; D000093542:Gemcitabine