title: Population pharmacokinetics of gemcitabine and its metabolite in Japanese cancer patients: impact of genetic polymorphisms.
abstract: OBJECTIVE
  Gemcitabine (2',2'-difluorodeoxycytidine) is an anticancer drug, which is effective against solid tumours, including non-small-cell lung cancer and pancreatic cancer. After gemcitabine is transported into cells by equilibrative and concentrative nucleoside transporters, it is phosphorylated by deoxycytidine kinase (DCK) and further phosphorylated to its active diphosphorylated and triphosphorylated forms. Gemcitabine is rapidly metabolized by cytidine deaminase (CDA) to an inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), which is excreted into the urine. Toxicities of gemcitabine are generally mild, but unpredictable severe toxicities such as myelosuppression and interstitial pneumonia are occasionally encountered. The aim of this study was to determine the factors, including genetic polymorphisms of CDA, DCK and solute carrier family 29A1 (SLC29A1 [hENT1]), that alter the pharmacokinetics of gemcitabine in Japanese cancer patients.
  
  
  METHODS
  250 Japanese cancer patients who received 30-minute intravenous infusions of gemcitabine at 800 or 1000 mg/m2 in the period between September 2002 and July 2004 were recruited for this study. However, four patients were excluded from the final model built in this study because they showed bimodal concentration-time curves. Two patients who experienced gemcitabine-derived life-threatening toxicities in October 2006 and January 2008 were added to this analysis. One of these patients received 30-minute intravenous infusions of gemcitabine at 454 mg/m2 instead of the usual dose (1000 mg/m2). Plasma concentrations of gemcitabine and dFdU were measured by high-performance liquid chromatography-photodiode array/mass spectrometry. In total, 1973 and 1975 plasma concentrations of gemcitabine and dFdU, respectively, were used to build population pharmacokinetic models using nonlinear mixed-effects modelling software (NONMEM version V level 1.1).
  
  
  CONCLUSIONS
  Two-compartment models fitted well to plasma concentration-time curves for both gemcitabine and dFdU. Major contributing factors for gemcitabine clearance were genetic polymorphisms of CDA, including homozygous CDA*3 [208G>A (Ala70Thr)] (64% decrease), heterozygous *3 (17% decrease) and CDA -31delC (an approximate 7% increase per deletion), which has a strong association with CDA*2 [79A>C (Lys27Gln)], and coadministered S-1, an oral, multicomponent anti-cancer drug mixture consisting of tegafur, gimeracil and oteracil (an approximate 19% increase). The estimated contribution of homozygous CDA*3 to gemcitabine clearance provides an explanation for the life-threatening severe adverse reactions, including grade 4 neutropenia observed in three Japanese patients with homozygous CDA*3. Genetic polymorphisms of DCK and SLC29A1 (hENT1) had no significant correlation with gemcitabine pharmacokinetic parameters. Aging and increased serum creatinine levels correlated with decreased dFdU clearance.
  
  
  CONCLUSIONS
  A population pharmacokinetic model that included CDA genotypes as a covariate for gemcitabine and dFdU in Japanese cancer patients was successfully constructed. The model confirms the clinical importance of the CDA*3 genotype.
authors.affiliation: Project Team for Pharmacogenetics, National Institute of Health Sciences, Tokyo, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Sugiyama
authors.forename: Nahoko
authors.initials: N
authors.lastname: Kaniwa
authors.forename: Su-Ryang
authors.initials: SR
authors.lastname: Kim
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Hasegawa
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.forename: Hideki
authors.initials: H
authors.lastname: Ueno
authors.forename: Takuji
authors.initials: T
authors.lastname: Okusaka
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ikeda
authors.forename: Chigusa
authors.initials: C
authors.lastname: Morizane
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kondo
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Tomohide
authors.initials: T
authors.lastname: Tamura
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Yoshida
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Sawada
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D044466:Asian People; D003198:Computer Simulation; D003564:Cytidine Deaminase / Q000235:genetics*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D003842:Deoxycytidine Kinase / Q000235:genetics; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics; D005260:Female; D005467:Floxuridine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D011110:Polymorphism, Genetic; 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; D003564:Cytidine Deaminase; C084565:2',2'-difluoro-2'-deoxyuridine; D000093542:Gemcitabine