Equilibrative nucleoside transporter 1 genotype, cytidine deaminase activity and age predict gemcitabine plasma clearance in patients with solid tumours |
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Authors: | Gusella Milena Pasini Felice Bolzonella Caterina Meneghetti Silvia Barile Carmen Bononi Antonio Toso Silvia Menon Daniela Crepaldi Giorgio Modena Yasmina Stievano Laura Padrini Roberto |
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Affiliation: | 1Laboratorio di Farmacologia e Biologia Molecolare, Via Ugo Grisetti 265, 45027 Trecenta, Italy;2Struttura Complessa di Oncologia, Dipartimento Oncologico, Ospedale Santa Maria della Misericordia, Viale Tre Martiri 89, 45100 Rovigo, Italy;3Istituto Oncologico Veneto, Via Gattamelata, 64 35128 Padova, Italy;4Dipartimento di Medicina Clinica e Sperimentale, Università of Padova, via Giustiniani 2, 35128 Padova, Italy |
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Abstract: |
AIMGemcitabine (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.METHODSForty-seven patients received GEM 1000–1250 mg m−2 i.v. over 30 min. 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.RESULTSMultivariate 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,∞)) (r2= 0.77).CONCLUSIONSOur 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. |
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Keywords: | cytidine deaminase deoxycytidine kinase gemcitabine nucleoside transporter pharmacogenetics pharmacokinetics |
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