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The small-molecule tyrosine kinase inhibitor nilotinib is a potent noncompetitive inhibitor of the SN-38 glucuronidation by human UGT1A1

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Abstract

Purpose

Inhibition of the UDP-glucuronosyltransferase (UGT) 1A1 by nilotinib was examined in vitro with SN-38 as a substrate, to estimate the possibility of drug–drug interaction of nilotinib with other medicines predominantly detoxified by UGT1A1.

Methods

Inhibition of UGT1A1-catalyzed SN-38 glucuronidation by nilotinib was examined with human liver microsomes (HLM) and recombinant human UGT1A1 as enzyme sources. Inhibition constants (K i) were estimated with kinetic analysis.

Results

Nilotinib potently inhibited the SN-38 glucuronidation by human liver microsomal UGT1A1 and recombinant UGT1A1 in a noncompetitive manner, with K i values of 0.286 ± 0.0094 and 0.079 ± 0.0029 μM, respectively. If a drug that serves as a substrate of UGT1A1 is administered with nilotinib, the area under the plasma concentration–time curve of a drug estimated by using these K i values would be two times or higher than that without nilotinib, suggesting drug–drug interactions involving UGT1A1. These in vitro data and the prediction of drug–drug interaction are helpful for the clinical management of the nilotinib use.

Conclusion

We found that nilotinib is a potent noncompetitive inhibitor of human UGT1A1 activity.

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Acknowledgments

We sincerely thank Drs. Yu, Sunakawa, Hiroo Ishida, Keishi Yamashita, Keiko Mizuno, Taro Yokoyama, Ken Shiozawa, Keisuke Miwa, Shigehira Saji, and Takashi Hirose for the valuable discussion on the present analyses. This study was supported in part by the Grant-in-Aid for Cancer Research 21S-8-1 from the Ministry of Health, Labour and Welfare of Japan, and in part by a grant-in-aid for “Support Project of Strategic Research Center in Private Universities” from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) to Saitama Medical University Research Center for Genomic Medicine.

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Authors and Affiliations

  1. Department of Medical Oncology, International Medical Center, Comprehensive Cancer Center, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1298, Japan

    Ken-ichi Fujita, Minako Sugiyama, Yuko Akiyama & Yasutsuna Sasaki

  2. Project Research Laboratory, Research Center for Genomic Medicine, Saitama Medical University, 1397-1 Yamane, Hidaka, Saitama, 350-1241, Japan

    Ken-ichi Fujita, Minako Sugiyama, Yuko Akiyama & Yasutsuna Sasaki

  3. Department of Clinical Oncology and Chemotherapy, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8560, Japan

    Yuichi Ando

Authors
  1. Ken-ichi Fujita
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  2. Minako Sugiyama
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  3. Yuko Akiyama
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  4. Yuichi Ando
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  5. Yasutsuna Sasaki
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Corresponding author

Correspondence to Ken-ichi Fujita.

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Fujita, Ki., Sugiyama, M., Akiyama, Y. et al. The small-molecule tyrosine kinase inhibitor nilotinib is a potent noncompetitive inhibitor of the SN-38 glucuronidation by human UGT1A1. Cancer Chemother Pharmacol 67, 237–241 (2011). https://doi.org/10.1007/s00280-010-1445-3

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  • DOI: https://doi.org/10.1007/s00280-010-1445-3

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