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Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients

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Abstract

Purpose

Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to “UGT1A1*28 or *6” on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated.

Methods

Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time–concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan–cisplatin-combination therapy (62 patients).

Results

Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 −1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T (# IIB) and SLCO1B1 521T>C (V174A) (*15 · 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 # IIB, SLCO1B1*15 · 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory.

Conclusions

Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.

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Acknowledgments

This study was supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, and by the Program for the Promotion of Studies in Health Sciences of the Ministry of Health, Labor and Welfare of Japan. We thank Yakult Honsha Co., Ltd (Tokyo, Japan) for providing analytical standards of irinotecan and its metabolites. We also thank Ms. Chie Sudo for her administrative assistance.

Author information

Author notes

  1. Kuniaki Shirao

    Present address: Department of Medical Oncology, OITA University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, 879-5593, Japan

  2. Hironobu Minami

    Present address: Medical Oncology, Department of Medicine, Kobe University Hospital and Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

Authors and Affiliations

  1. Division of Functional Biochemistry and Genomics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Kimie Sai, Yoshiro Saito, Keiko Maekawa, Tomoko Nishimaki-Mogami & Jun-ichi Sawada

  2. Project Team for Pharmacogenetics, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Su-Ryang Kim

  3. Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Nahoko Kaniwa

  4. Division of Internal Medicine, National Cancer Center Hospital, 5-1-5 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Kuniaki Shirao, Tetsuya Hamaguchi, Noboru Yamamoto, Hideo Kunitoh, Yuichiro Ohe, Yasuhide Yamada & Tomohide Tamura

  5. Genomics Division, National Cancer Center Research Institute, 5-1-5 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Teruhiko Yoshida

  6. Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Yasuhiro Matsumura

  7. Division of GI Oncology/Digestive Endoscopy, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Atsushi Ohtsu

  8. National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Nagahiro Saijo

  9. Division of Oncology/Hematology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan

    Hironobu Minami

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  1. Kimie Sai
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  2. Yoshiro Saito
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Correspondence to Kimie Sai.

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Sai, K., Saito, Y., Maekawa, K. et al. Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients. Cancer Chemother Pharmacol 66, 95–105 (2010). https://doi.org/10.1007/s00280-009-1138-y

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