首页 | 本学科首页   官方微博 | 高级检索  
     


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

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 1000–1250 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.

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,∞)) (r2= 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.
Keywords:cytidine deaminase   deoxycytidine kinase   gemcitabine   nucleoside transporter   pharmacogenetics   pharmacokinetics
本文献已被 PubMed 等数据库收录!
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司  京ICP备09084417号