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Cancer Chemotherapy and Pharmacology

, Volume 83, Issue 5, pp 993–998 | Cite as

Pazopanib interacts with irinotecan by inhibiting UGT1A1-mediated glucuronidation, but not OATP1B1-mediated hepatic uptake, of an active metabolite SN-38

  • Mariko Iwase
  • Ken-ichi FujitaEmail author
  • Yuki Nishimura
  • Natsumi Seba
  • Yusuke Masuo
  • Hiroo Ishida
  • Yukio Kato
  • Yuji Kiuchi
Short Communication
  • 63 Downloads

Abstract

Purpose

Pazopanib is an orally active, multi-targeted tyrosine kinase inhibitor. A previous phase I study demonstrated that coadministration of pazopanib with irinotecan increases the area under the plasma concentration–time curve (AUC) for SN-38, an active metabolite of irinotecan. To clarify the possible mechanism underlying that drug–drug interaction, we investigated the potential for pazopanib to inhibit UDP-glucuronosyltransferase (UGT)1A1 and organic anion-transporting polypeptide (OATP)1B1, which are involved in detoxification and hepatic uptake of SN-38, respectively.

Methods

Human liver microsomes (HLMs) and recombinant human UGT1A1, and HEK293 cells stably transfected with OATP1B1 were used to evaluate the inhibitory effects of pazopanib against glucuronidation, and hepatic uptake of SN-38, respectively. Kinetic analysis was performed to estimate inhibition constants, which were corrected for non-specific binding to enzyme sources (Ki,u values).

Results

Concentration-dependent inhibition of SN-38 glucuronidation was observed in the HLMs and recombinant human UGT1A1 experiments: Pazopanib noncompetitively inhibited SN-38 glucuronidation by HLMs (Ki,u = 1.6 ± 0.05 µM) and recombinant human UGT1A1 (Ki,u = 0.69 ± 0.02 µM). Pazopanib-induced increases in SN-38 AUC estimated using Ki,u values were comparable to those observed in patients of the phase I study who received both irinotecan and pazopanib. Such results suggest that the drug–drug interaction is at least partially mediated by inhibition of UGT1A1. In contrast, pazopanib did not inhibit OATP1B1-mediated SN-38 uptake at concentrations up to 60 µM.

Conclusions

Results showed that pazopanib inhibits UGT1A1-mediated SN-38 glucuronidation, but not OATP1B1-mediated SN-38 uptake.

Keywords

Pazopanib UGT1A1 SN-38 Pharmacokinetics Drug–drug interaction 

Notes

Acknowledgements

This study was supported in part by a Grant-in-Aid for Scientific Research (C) [16K08918 to H.I.] from the Japan Society for the Promotion of Science (JSPS).

Compliance with ethical standards

Conflict of interest

We have no conflict of interest to declare.

Ethical standards

No human and/or animal studies were performed in this study.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Mariko Iwase
    • 1
  • Ken-ichi Fujita
    • 2
    • 3
    Email author
  • Yuki Nishimura
    • 1
  • Natsumi Seba
    • 4
  • Yusuke Masuo
    • 4
  • Hiroo Ishida
    • 5
  • Yukio Kato
    • 4
  • Yuji Kiuchi
    • 1
  1. 1.Department of PharmacologyShowa University School of MedicineTokyoJapan
  2. 2.Institute of Molecular OncologyShowa UniversityTokyoJapan
  3. 3.Division of Cancer Cell Biology, Department of Pharmaceutical ScienceShowa University School of PharmacyTokyoJapan
  4. 4.Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health SciencesKanazawa UniversityKanazawaJapan
  5. 5.Division of Medical Oncology, Department of MedicineShowa University School of MedicineTokyoJapan

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