Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours.

AIM 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.

[1]  F. Innocenti,et al.  Clinical pharmacology and pharmacogenetics of gemcitabine , 2009, Drug metabolism reviews.

[2]  John R. Mackey,et al.  Human Equilibrative Nucleoside Transporter 1 and Human Concentrative Nucleoside Transporter 3 Predict Survival after Adjuvant Gemcitabine Therapy in Resected Pancreatic Adenocarcinoma , 2009, Clinical Cancer Research.

[3]  M. Links,et al.  Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate. , 2008, British journal of clinical pharmacology.

[4]  J. Schellens,et al.  Prolonged versus standard gemcitabine infusion: translation of molecular pharmacology to new treatment strategy. , 2008, The oncologist.

[5]  M. Links,et al.  Randomized crossover study evaluating the effect of gemcitabine infusion dose rate: evidence of auto-induction of gemcitabine accumulation. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  J. Hayashi,et al.  In situ hybridization and immunolocalization of concentrative and equilibrative nucleoside transporters in the human intestine, liver, kidneys, and placenta. , 2007, American journal of physiology. Regulatory, integrative and comparative physiology.

[7]  C. Lanz,et al.  Rapid determination of gemcitabine in plasma and serum using reversed-phase HPLC. , 2007, Journal of separation science.

[8]  Takashi Ishikawa,et al.  Human equilibrative nucleoside transporter 1 is associated with the chemosensitivity of gemcitabine in human pancreatic adenocarcinoma and biliary tract carcinoma cells. , 2007, Oncology reports.

[9]  Matthew Links,et al.  A phase 1 and pharmacokinetic study of gemcitabine and oxaliplatin in patients with solid tumors , 2006, Cancer Chemotherapy and Pharmacology.

[10]  R. Ferrell,et al.  Functional single nucleotide polymorphism haplotypes in the human equilibrative nucleoside transporter 1 , 2006, Pharmacogenetics and genomics.

[11]  Franco Mosca,et al.  Transcription analysis of human equilibrative nucleoside transporter-1 predicts survival in pancreas cancer patients treated with gemcitabine. , 2006, Cancer research.

[12]  H. Ueno,et al.  Pharmacokinetics of gemcitabine in Japanese cancer patients: the impact of a cytidine deaminase polymorphism. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[13]  H. Ueno,et al.  Severe Drug Toxicity Associated with a Single-Nucleotide Polymorphism of the Cytidine Deaminase Gene in a Japanese Cancer Patient Treated with Gemcitabine plus Cisplatin , 2005, Clinical Cancer Research.

[14]  S. Mahieu,et al.  Cytidine deaminase in polymyalgia rheumatica and elderly onset rheumatoid arthritis , 2005, Clinical Rheumatology.

[15]  John R. Mackey,et al.  The Absence of Human Equilibrative Nucleoside Transporter 1 Is Associated with Reduced Survival in Patients With Gemcitabine-Treated Pancreas Adenocarcinoma , 2004, Clinical Cancer Research.

[16]  Ryuzo Ueda,et al.  Determinants of sensitivity and resistance to gemcitabine: The roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non‐small cell lung cancer , 2004, Cancer science.

[17]  Conrad C. Huang,et al.  Functional and genetic diversity in the concentrative nucleoside transporter, CNT1, in human populations. , 2004, Molecular pharmacology.

[18]  L. Mangravite,et al.  Nucleoside transporters in the disposition and targeting of nucleoside analogs in the kidney. , 2003, European journal of pharmacology.

[19]  J. Mackey,et al.  Nucleoside anticancer drugs: the role of nucleoside transporters in resistance to cancer chemotherapy† , 2003, Oncogene.

[20]  G. Curigliano,et al.  Drug distribution and pharmacokinetic/pharmacodynamic relationship of paclitaxel and gemcitabine in patients with non-small-cell lung cancer. , 2001, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  I. Coe,et al.  Differential expression of human nucleoside transporters in normal and tumor tissue. , 2001, Biochemical and biophysical research communications.

[22]  C. R. Crawford,et al.  Functional nucleoside transporters are required for gemcitabine influx and manifestation of toxicity in cancer cell lines. , 1998, Cancer research.

[23]  H. Ishitsuka,et al.  Design of a novel oral fluoropyrimidine carbamate, capecitabine, which generates 5-fluorouracil selectively in tumours by enzymes concentrated in human liver and cancer tissue. , 1998, European journal of cancer.

[24]  S. Watanabe,et al.  Expression of cytidine deaminase in human solid tumors and its regulation by 1 alpha,25-dihydroxyvitamin D3. , 1996, Biochimica et biophysica acta.

[25]  P. Davis,et al.  Serum cytidine deaminase as a measure of disease activity in rheumatoid arthritis and systemic lupus erythematosus. , 1993, Journal of Rheumatology.

[26]  J. Laliberté,et al.  Kinetic studies on 2',2'-difluorodeoxycytidine (Gemcitabine) with purified human deoxycytidine kinase and cytidine deaminase. , 1993, Biochemical pharmacology.

[27]  H. Kantarjian,et al.  Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[28]  S. Mineishi,et al.  A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. , 1991, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  Adam P Dicker,et al.  Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer. , 2009, Gastroenterology.

[30]  G. Peters,et al.  Deoxycytidine kinase and deoxycytidine deaminase activities in human tumour xenografts. , 1993, European journal of cancer.