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

Emiko Sugiyama, Nahoko Kaniwa, Su-Ryang Kim, Ruri Kikura-Hanajiri, Ryuichi Hasegawa, Keiko Maekawa, Yoshiro Saito, Shogo Ozawa, Jun-ichi Sawada, Naoyuki Kamatani, Junji Furuse, Hiroshi Ishii, Teruhiko Yoshida, Hideki Ueno, Takuji Okusaka, Nagahiro Saijo

From the Project Team for Pharmacogenetics; Divisions of Medicinal Safety Sciences, Pharmacognosy and Phytochemistry, Biochemistry and Immunochemistry, and Pharmacology, National Institute of Health Sciences; Division of Genomic Medicine, Department of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University; Genetics Division, Research Institute, National Cancer Center, Tokyo; and Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital East, Kashiwa, Japan

Address reprint requests to Nahoko Kaniwa, PhD, Division of Medicinal Safety Sciences, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan; e-mail: nkaniwa{at}nihs.go.jp

Purpose Gemcitabine is rapidly metabolized to its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), by cytidine deaminase (CDA). We previously reported that a patient with homozygous 208A alleles of CDA showed severe adverse reactions with an increase in gemcitabine plasma level. This study extended the investigation of the effects of CDA genetic polymorphisms on gemcitabine pharmacokinetics and toxicities.

Patients and Methods Genotyping of CDA was performed by a direct sequencing of DNA obtained from the peripheral blood of Japanese gemcitabine-naïve cancer patients (n = 256). The patients recruited to the association study received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m², and eight blood samples were periodically collected (n = 250). Plasma levels of gemcitabine and dFdU were measured by high-performance liquid chromatography. Plasma CDA activities toward cytidine and gemcitabine were also measured (n = 121).

Results Twenty-six genetic variations, including 14 novel ones and two known nonsynonymous single nucleotide polymorphisms (SNPs), were detected. Haplotypes harboring the nonsynonymous SNPs 79A>C (Lys27Gln) and 208G>A (Ala70Thr) were designated *2 and *3, respectively. The allelic frequencies of the two SNPs were 0.207 and 0.037, respectively. Pharmacokinetic parameters of gemcitabine and plasma CDA activities significantly depended on the number of haplotype *3. Haplotype *3 was also associated with increased incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin, or carboplatin. Haplotype *2 showed no significant effect on gemcitabine pharmacokinetics.

Conclusion 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.

Supported by the Program for the Promotion of Fundamental Studies in Health Sciences (Grant No. MPJ6 and 05-25), and the Health and Labour Sciences Research Grant on Human Genome and Tissue Engineering (Grant No. H16-Genome-008) from the Ministry of Health, Labour, and Welfare of Japan.

Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL, and at the 13th Annual Meeting of the North American Society for the Study of Xenobiotics, October 22-27, 2005, Maui, HI.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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• Genotype-Based Methods for Anticipating Gemcitabine-Related Severe Toxicities May Lead to False-Negative Results
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