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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

	ABSTRACT

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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.

	INTRODUCTION

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Gemcitabine (2',2'-difluorodeoxycytidine) is a nucleoside anticancer drug that has a broad spectrum of antitumor activity against various solid tumors, such as non–small-cell lung cancer and pancreatic cancer.¹ In a randomized clinical trial, gemcitabine was confirmed to provide a survival advantage over fluorouracil in addition to symptom-relieving benefits in patients with advanced pancreatic cancer.² On the basis of these results, gemcitabine has generally been accepted as a standard chemotherapeutic agent for advanced pancreatic cancer.

Gemcitabine is transported into cells by concentrative and equilibrative nucleoside transporters,^3-8 where it is phosphorylated to its monophosphate form by deoxycytidine kinase. Gemcitabine triphosphate, an active form of gemcitabine, is incorporated into an elongating DNA strand, and is followed by the addition of another deoxynucleotide that leads to the halt of DNA synthesis.^9,10 Another mode of action in solid tumors, associated with the inhibition of ribonucleotide reductase, has also been suggested.¹¹

Gemcitabine is rapidly metabolized to an inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU) by cytidine deaminase (CDA),⁹ and most of an administered dose is recovered as dFdU in the urine.¹² CDA is expressed at varying levels in the human tissues,¹³ and the rapid clearance of gemcitabine can be attributed to its plentiful occurrence in the liver.¹⁴ Two single nucleotide polymorphisms (SNPs), 79A>C (Lys27Gln) and 435T>C (Thr145Thr), have been discovered in CDA, the CDA-encoding gene in humans.^15,16 The 79A>C SNP reportedly reduces the deamination activity (maximum velocity/Km) toward 1-beta-D-arabinofuranosyl cytosine (cytarabine),¹⁵ and increases Km toward gemcitabine,¹⁷ in vitro. A recently discovered third SNP, 208G>A (Ala70Thr) displayed a decrease in deamination activity of 60% for cytidine and 68% for cytarabine when introduced into a CDA-null yeast strain.¹⁸

Toxicity of gemcitabine is generally mild,^19,20 but unpredictable severe toxicities such as myelosuppression are occasionally experienced.^21,22 Our previous case report described a patient with homozygous 208A alleles of the CDA gene who showed severe adverse reactions with increased plasma gemcitabine levels.²³ In addition, there has been controversy over the relationship between cellular CDA activity and the clinical effects of cytarabine.^24-27 This study examined the relationship between CDA polymorphisms, and the pharmacokinetics of gemcitabine, plasma CDA activity, or adverse reactions in Japanese cancer patients.

	PATIENTS AND METHODS

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Gemcitabine and dFdU for analytic standards were supplied by Eli Lilly Japan K.K. (Kobe, Japan). Tetrahydrouridine, 3'-deoxy-3'-fluoro-thymidine (3'-dFT), cytidine and uridine (Sigma-Aldrich Chemical Co, St Louis, MO) were purchased. All other chemicals were of highest grade available.

Patients
The participants in this study consisted of 256 Japanese patients with carcinoma, including six patients described in a previous report,²³ at the National Cancer Center Hospital (Tokyo, Japan) and National Cancer Center Hospital East (Kashiwa, Japan). Two hundred fifty-one patients received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m², and five patients received a fixed dose-rate (10 mg/m²/min) infusion at a dose between 1,000 and 1,500 mg/m². The eligibility criteria for the study were as previously reported.²³ The ethics committees of the National Cancer Center and the National Institutes of Health Sciences approved this study. Written informed consent was obtained from each participant.

Monitoring and Toxicities
A complete medical history and data on physical examinations were recorded before the gemcitabine therapy. CBC and platelet counts, as well as blood chemistry, were measured once a week during the first 2 months of gemcitabine treatment. Toxicities were graded according to the National Cancer Institute Common Toxicity Criteria, version 2.

DNA Sequencing
All four exons and the 5'-upstream region (approximately 800 base pairs [bp] from the translation initiation codon) of CDA were amplified from 100 ng of DNA extracted from peripheral blood, and sequenced along both strands. Polymerase chain reaction (PCR) primers²³ and sequencing and PCR conditions²⁸ were described previously. For detection of an approximately 300-bp Alu insertion (IVS3-194_-193insAlu), PCR was performed using a specific primer set (5'- TTGTCATAGCAGAAGGAGGTT-3' and 5'- TCAGCTCTCCACACCATAAGG-3') and 100 ng of DNA as a template. Then, sizes of the amplified fragments were determined by 1% agarose gel electrophoresis. NT_004610.17 (GenBank, National Center for Biotechnology Information, Bethesda, MD) was used as the reference sequence.

Linkage Disequilibrium and Haplotype Analyses
Hardy-Weinberg equilibrium and linkage disequilibrium (LD) analyses were performed by SNPAlyze software (Dynacom Co, Yokohama, Japan). All of the detected variations were found to be in Hardy-Weinberg equilibrium (P .05), except for the SNP IVS1+37G>A (P = .002). Some of the haplotypes were unambiguously assigned from subjects with homozygous variations at all sites or a heterozygous variation at only one site. The diplotype configurations (a combination of haplotypes) were separately inferred by LDSUPPORT software,²⁹ which determines the posterior probability distribution of the diplotype configuration for each subject based on the estimated haplotype frequencies. The diplotype configurations of all but 11 subjects were inferred with probability of more than 0.93. All haplotypes inferred in single subjects were gathered as the groups "Other *1" and "Other *2" in Table 1.

CDA Activities in Plasma
Determination of CDA activities was performed using the method by Richards et al³⁰ with slight modifications (modifications are as follows: gemcitabine was used as a substrate as well as cytidine, internal standards for analysis [3'-dFT for gemcitabine or dFdU for cytidine] were added to the mixtures at the beginning of the reaction, and high-performance liquid chromatography was used for detection of reaction products). CDA activity was expressed by unit, and one unit of enzyme activity was defined as the concentration that produces 0.1 nmol of dFdU or uridine per minute per milliliter of plasma.³⁰

Statistical Analysis
Kruskal-Wallis, Mann-Whitney, and Pearson's correlation tests were performed using the JMP software (SAS Institute Inc, Cary, NC). Two ordinally scaled categoric data were subjected to ² analysis for a correlation test. A significance level of .05 was applied to all two-tailed and correlation tests. Multiplicity was adjusted by the false-discovery rate,³¹ if necessary.

	RESULTS

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Genetic Variations and Haplotype Structures of CDA
Twenty-six (14 novel) genetic variations were detected in the 256 Japanese cancer patients enrolled onto this study (Table 2). Three of the novel variations were found in the 5'-untranslated region, one in exon 2, three in the 3'-untranslated region and seven in the introns. Three known SNPs in the coding region of CDA were also detected. Among these, the nonsynonymous SNPs, 79A>C (Lys27Gln) and 208G>A (Ala70Thr), exhibited allelic frequencies of 0.207 and 0.037 (Table 2), respectively, and they were comparable to those reported previously.¹⁸ One patient was found to be homozygous for the 208A polymorphism. A novel insertion of an approximately 320-bp Alu element (IVS3-194_-193insAlu) was newly found in intron 3.

View larger version (32K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Linkage disequilibrium (LD) among 26 CDA variations. Pairwise LD as r2 (from 0 to 1) is expressed as 10-graded blue color. The density of the blue color increases with higher linkage rates.

Effects of Patient Background Factors on Gemcitabine Pharmacokinetics
Characteristics of the 250 patients recruited for the pharmacokinetic study are shown in Table 3. As previously reported, the patient who was homozygous for 208A showed extraordinarily high gemcitabine and low dFdU plasma concentrations.²³ Therefore, this patient was excluded when effects of patient background factors on the pharmacokinetic parameters of gemcitabine were analyzed.

After careful examination, the data did not identify any *1, *2, or *3 subtypes that showed statistically significant differences from each major subtype within the three groups (Table 5; unpublished data). Therefore, each subtype was combined into one group (the *1, *2, or *3 group) to investigate the association between pharmacokinetic parameters and genetic groups.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Effects of haplotypes *2 and *3 on the pharmacokinetic parameters of gemcitabine. (A) Peak concentration (Cmax) and (B) area under the curve (AUC) were corrected assuming that all patients received 1,000 mg/m2 of gemcitabine. (C) Clearance (CL/m2). Each point corresponds to an individual patient. The bars denote the median values. P values are from Dunn's multiple comparison test.

Haplotype *2 failed to show any significant effects on the plasma CDA activities toward both gemcitabine and cytidine. On the other hand, activity decreased depending on the number of haplotype *3 (Table 6; Fig 3). The plasma CDA activities in the homozygous *3 (208A) patient were 12% (gemcitabine) and 25% (cytidine) of the median activities for the *1/*1 patients. As shown in Figure 4, a statistically significant correlation between the plasma CDA activity toward gemcitabine and the AUC values of gemcitabine was observed (r = –0.30; P = .0009). However, the correlations were not remarkable.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Effects of haplotypes *2 and *3 on plasma cytidine deaminase (CDA) activity toward gemcitabine and cytidine substrates. (A) Gemcitabine was used as a substrate, and (B) cytidine was used as a substrate. Each point corresponds to an individual patient. The bars denote the median values.

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Correlation between plasma area under the curve (AUC) and cytidine deaminase (CDA) activity toward gemcitabine. AUC was corrected assuming that all patients received 1,000 mg/m2 of gemcitabine. The inset excludes the data obtained from a homozygous *3 carrier. The correlation coefficient is –0.31 when the homozygous *3 carrier is included and –0.28 when the carrier is excluded.

	DISCUSSION

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Human CDA is involved in the salvaging of pyrimidines,^33,34 and plays a key role in detoxifying gemcitabine. Although the activities of 27Gln or 70Thr variant (the products of 79A>C or 208G>A) toward cytidine and cytarabine were reported to be lower than those of the "prototype" in a yeast expression system,¹⁸ the decreased CDA activity in patients bearing these SNPs has not been reported. Kreis et al³⁵ reported that the response of leukemic patients to cytarabine correlated with the phenotype of CDA deamination determined based on the ratio of plasma concentrations of a cytarabine metabolite and cytarabine.³⁵ They reported that 70% of subjects were slow metabolizers. However, the relationship between genetic polymorphisms and phenotypes remained to be clarified.

In our study, the haplotype *2 harboring 79C (27Gln) did not show clear effects on the AUC and CL/m² values. In contrast, the 208A (Thr70, *3) -dependent decreases in gemcitabine clearance and plasma CDA activities were clearly demonstrated in this study. These results suggest that the CDA variant loses its in vivo deamination activities toward gemcitabine considerably. Moreover, the decreased plasma CDA activities toward gemcitabine and cytidine ex vivo also strongly suggest that the reduced enzymatic activity was caused by the genetic variation.

In the monotherapy group, the increased AUC in the patient with haplotype *3 did not clearly augment the incidence of toxicities including neutropenia. However, the incidences of grade 3 or higher neutropenia were higher in patients heterozygous for haplotype *3 compared with in the patients without haplotype *3 when they received concomitant chemotherapy with fluorouracil or platinum compounds. As we reported recently, one patient homozygous for haplotype *3 who received both gemcitabine and cisplatin suffered from extremely severe adverse effects including grade 3 anathema.²³ However, he experienced neither of the specific toxicities associated with cisplatin, nephrotoxicity, and neurotoxicity. Abbruzzese et al³⁶ reported the gemcitabine dose-dependent increase in incidence of thrombocytopenia (one of seven at 525 mg/m²/wk, three of nine at 790 mg/m²/wk, and three of six at 1,000 mg/m²/wk).³⁶ Therefore, we concluded that extremely high exposure to gemcitabine (AUC five times higher than the average) due to the decreased deamination activity caused the life-threatening severe toxicities in this patient. In contrast, the gemcitabine AUC of the patients with heterozygous haplotype *3 was only slightly (23% to 48%) increased from that of the patients having no haplotype *3 (Table 6). This finding coincides with the lack of life-threatening severe toxicities in the heterozygotes for *3, although the incidences of grade 3 or higher neutropenia in the heterozygotes in combined chemotherapy groups were higher in the group without haplotype *3.

CDA is also involved in the activation of capecitabine to its active form fluorouracil.³⁷ Therefore, capecitabine activation would be inefficient in patients who are homozygous for 208A. The allele frequency of the 208G>A SNP, a tagging SNP of haplotype *3, was reported to be 0.125 in Africans, while it was not detected in Europeans.³⁸ The frequency of homozygous carriers of the variant could be higher in Africans than in the Japanese population. However, the frequency of 208G>A in Africans is still controversial, because it was not detected in 60 African Americans in a recent report.¹⁷ Extra attention may be necessary for patients with the allele before treatments with gemcitabine or cytarabine are initiated, especially to *3/*3 patients, although more studies are necessary to confirm the clinical importance of this allele in the treatments using gemcitabine or cytarabine.

A number of studies have investigated the associations between cellular CDA activity and drug responses to cytarabine.^24-27,39 However, correlation between plasma CDA activity and the pharmacokinetics of gemcitabine has not been reported. Plasma CDA activity may be a useful biomarker to screen patients with a markedly decreased metabolic CDA activity such as the patient homozygous for the *3 allele found in our study, who showed extremely low plasma CDA activity. However, a very low contribution of plasma CDA to the total clearance of gemcitabine was reported,³⁶ and the plasma CDA levels are increased in the inflammatory diseases.^30,40 These may account for the failure in obtaining good correlations between plasma CDA activity and the pharmacokinetic parameters of gemcitabine, as shown in Figure 4.

In conclusion, we analyzed the CDA genetic variations and haplotypes in Japanese cancer patients who received gemcitabine. We then investigated the associations between genetic polymorphisms and the pharmacokinetics of gemcitabine or toxicities. Depending on the haplotype *3 harboring 208A, the metabolic clearance of gemcitabine decreased, and AUC and C_max values were increased. Moreover, plasma CDA activities correlated well with the CDA genotypes. The clinical importance of the SNP 208G>A, especially of homozygotes, should be confirmed by prospective clinical studies because only one homozygous *3 patient was found in this study.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Nagahiro Saijo, Chugai, AstraZeneca, Bristol-Myers Squibb Co Research Funds: Nagahiro Saijo, Bristol-Myers Squibb Co Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Nahoko Kaniwa, Shogo Ozawa, Jun-ichi Sawada, Naoyuki Kamatani, Hideki Ueno, Takuji Okusaka, Nagahiro Saijo

Financial support: Jun-ichi Sawada, Teruhiko Yoshida, Nagahiro Saijo

Administrative support: Nahoko Kaniwa, Ryuichi Hasegawa, Yoshiro Saito, Shogo Ozawa, Jun-ichi Sawada, Teruhiko Yoshida, Nagahiro Saijo

Provision of study materials or patients: Keiko Maekawa, Yoshiro Saito, Shogo Ozawa, Junji Furuse, Hiroshi Ishii, Hideki Ueno, Takuji Okusaka

Collection and assembly of data: Emiko Sugiyama, Su-Ryang Kim, Ruri Kikura-Hanajiri, Keiko Maekawa

Data analysis and interpretation: Emiko Sugiyama, Nahoko Kaniwa, Su-Ryang Kim, Yoshiro Saito, Junji Furuse, Hiroshi Ishii, Hideki Ueno, Takuji Okusaka

Manuscript writing: Emiko Sugiyama, Nahoko Kaniwa, Su-Ryang Kim, Hideki Ueno

Final approval of manuscript: Nahoko Kaniwa, Jun-ichi Sawada, Hideki Ueno, Nagahiro Saijo

	ACKNOWLEDGMENTS

 
We thank Emiko Jimbo, Miho Akimoto, Atsuko Watanabe, Tomoko Chujo, Makiyo Iwamoto, and Mamiko Shimada for assistance in sample collection and management, and Chie Sudo for secretarial assistance.

	NOTES

 
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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Submitted March 23, 2006; accepted August 25, 2006.

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  JCO 2007 25: 4855 [Full Text]

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