title: Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours.
abstract: OBJECTIVE
  Gemcitabine (GEM) enters normal and tumour cells via concentrative (CNT) and equilibrative nucleoside transporters (ENT) and is subsequently deaminated to the inactive difluorodeoxyurine (dFdU) by cytidine deaminase (CDA). The aim of our study was to ascertain whether the nucleoside transporter genotype and the CDA activity phenotype can predict total GEM plasma clearance.
  
  
  METHODS
  Forty-seven patients received GEM 1000-1250mgm(-2) i.v. over 30min. Plasma concentrations of GEM and dFdU were measured and individual pharmacokinetic profiles were determined. CDA activity was measured ex vivo in plasma samples. The two most common hENT1 and hCNT1 polymorphisms were determined from genomic DNA.
  
  
  RESULTS
  Multivariate analysis revealed that GEM plasma clearance (CL) was positively correlated with the end of infusion dFdU : GEM ratio (P < 0.0001), which is a marker of in vivo CDA activity. The ENT1 genotype characterized by high transport capacity (G/G) and age were inversely correlated with CL (P= 0.027 and 0.048, respectively). A strong correlation was found between end of infusion GEM concentration and area under the concentration-time curve from time 0 to infinity (AUC(0,∞)) (r(2) = 0.77).
  
  
  CONCLUSIONS
  Our results confirm the role of CDA and age on the interindividual variability of GEM CL and show the contribution of the hENT1 genotype for the first time.
authors.affiliation: Laboratorio di Farmacologia e Biologia Molecolare, Via Ugo Grisetti 265, 45027 Trecenta, Italy. milenagusella@libero.it
authors.forename: Milena
authors.initials: M
authors.lastname: Gusella
authors.forename: Felice
authors.initials: F
authors.lastname: Pasini
authors.forename: Caterina
authors.initials: C
authors.lastname: Bolzonella
authors.forename: Silvia
authors.initials: S
authors.lastname: Meneghetti
authors.forename: Carmen
authors.initials: C
authors.lastname: Barile
authors.forename: Antonio
authors.initials: A
authors.lastname: Bononi
authors.forename: Silvia
authors.initials: S
authors.lastname: Toso
authors.forename: Daniela
authors.initials: D
authors.lastname: Menon
authors.forename: Giorgio
authors.initials: G
authors.lastname: Crepaldi
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Modena
authors.forename: Laura
authors.initials: L
authors.lastname: Stievano
authors.forename: Roberto
authors.initials: R
authors.lastname: Padrini
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives; D033721:Equilibrative Nucleoside Transporter 1 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D011110:Polymorphism, Genetic; D044465:White People; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D033721:Equilibrative Nucleoside Transporter 1; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine