Pharmacokinetics of Gemcitabine in Japanese Cancer Patients: The Impact of a Cytidine Deaminase Polymorphism

Abstract

Haplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.

Cytidine deaminase single-nucleotide polymorphism is predictive of toxicity from gemcitabine in patients with pancreatic cancer: RTOG 9704

“…Pharmacokinetic parameters of gemcitabine, including decreased clearance of gemcitabine, and plasma CDA activities significantly correlated with the CDA Ala 70 Thr polymorphism but not the CDA Lys 27 Gln polymorphism, with the CDA Ala 70 Thr polymorphism being associated with an incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin or carboplatin. 24 Although this study showed a clear relationship between pharmacokinetic variables and the CDA Ala 70 Thr polymorphic variant, this haplotype has a frequency of only 3.7% in the Japanese population and has yet to be detected in Caucasians. 14 In fact, the frequency of homozygous variant CDA Gln 27 Gln in this study was 21%, making it a more common and clinically relevant CDA polymorphism.…”

Expression of gemcitabine- and cisplatin-related genes in non-small-cell lung cancer

“…19 However, functional genomics analysis showed a moderate decrease in CDA activity in the C79C variant with respect to the wildtype genotype, 49 and no effects of this polymorphism on gemcitabine pharmacokinetics were observed in a study carried out in 256 Japanese patients treated with gemcitabine. 50 These conflicting results suggest that genotype-phenotype correlation of CDA, as well as the role of this SNP in the pharmacokinetics/pharmacodynamics of gemcitabine is still unclear, and should be further evaluated with appropriate retrospective and prospective studies including analysis of genotype, gene expression and activity in tissues, pharmacokinetics and correlation with clinical outcome after gemcitabine therapy.…”

“…After an additional 24 h, total RNA was extracted using the QIAamp RNA Mini kit, and the cells were treated with gemcitabine (0.01-100 nM) for 48 h. At the end of drug treatment, the cell growth inhibitory effect of gemcitabine was studied by direct cell count using the trypan blue. Growth inhibition was expressed as the percentage of gemcitabine-untreated controls (untransfected and negativecontrol siRNA-treated cells), and the 50% inhibitory concentration of cell growth (IC 50 ) was calculated by nonlinear least squares curve fitting (GraphPad PRISM, Intuitive Software for Science, San Diego, CA, USA).…”

“…6,7 Gemcitabine is transported into the cells mostly by human equilibrative nucleoside transporter-1 (hENT1). 8 Basal expression levels of hENT1 were significantly correlated with the IC 50 values for gemcitabine in 22 NSCLC cell lines, 9 and cancer patients with higher hENT1 expression had longer survival after gemcitabine chemotherapy. 10,11 As a prodrug, gemcitabine must be phosphorylated to its active di-and triphosphate metabolites which, respectively, inhibit ribonucleotide reductase (RR) and DNA synthesis.…”

A new statistical screening approach for finding pharmacokinetics-related genes in genome-wide studies

“…Details of this analysis group were reported previously. 27 For gemcitabine PK analysis, 5 ml of heparinized blood was sampled before the first gemcitabine administration, and at 0, 15, 30, 60, 90, 120 and 240 min after the termination of the infusion. The AUC, mean residence time from 0 to infinity, peak concentration (C max ), clearance (CL m À2 ), distribution volume based on the terminal phase (Vz m À2 ) and elimination rate constant (K el ) were calculated using WinNonlin ver.…”