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

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Gemcitacine is taken up by the cell through various nucleoside transporters of either the concentrative (CNT) or equilibrative type (ENT) and is then transformed into the inactive metabolite, dFdU, by cytidine deaminase (CDA) and into the active metabolite, dFdCMP, by deoxycytidine kinase (dCK). • While the major contribution of CDA to gemcitabine elimination is well recognized no data about the role of CNT and ENT activities have yet been reported. Both nucleoside transporters exhibit genetic polymorphisms characterized by different expression levels or nucleoside affinity. WHAT THIS STUDY ADDS • The plasma clearance (CL) of gemcitabine has been determined following the standard 30 min infusion of 1000–1250 mg m−2. The in vivo CDA activity was measured as end of infusion metabolic ratio (MR = dFdU : gembitabine) and the variant hCNT-1 and hENT-1 alleles were genotyped. • Our results confirmed that gemcitabine CL is directly correlated with CDA activity and inversely correlated with age and, for the first time, show that patients heterozygous for the –706 G > C hENT-1 mutation have a lower CL as compared with wild type patients. 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.