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Prediction of Drug–Drug Interaction Between Dabrafenib and Irinotecan via UGT1A1-Mediated Glucuronidation

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Abstract

Background

Dabrafenib and irinotecan are two drugs that can be utilized to treat melanoma. A previous in vivo study has shown that dabrafenib enhances the antitumor activity of irinotecan in a xenograft model with unclear mechanism.

Objectives

This study aims to investigate the inhibition of dabrafenib on SN-38 (the active metabolite of irinotecan) glucuronidation, trying to elucidate the possible mechanism underlying the synergistic effect and to provide a basis for further development and optimization of this combination in clinical research.

Methods

Recombinant human uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and human liver microsomes (HLMs) were employed to catalyze the glucuronidation of SN-38 in vitro. Inhibition kinetic analysis and quantitative prediction study were combined to predict drug–drug interaction (DDI) potential in vivo.

Results

Dabrafenib noncompetitively inhibited SN-38 glucuronidation in pooled HLMs and recombinant UGT1A1 with unbound inhibitor constant (Ki,u) values of 12.43 ± 0.28 and 3.89 ± 0.40 μM, respectively. Based on the in vitro Ki,u value and estimation of kinetic parameters, dabrafenib administered at 150 mg twice daily may result in about a 1−2% increase in the area under the curve (AUC) of SN-38 in vivo. However, the ratios of intra-enterocyte concentration of dabrafenib to Ki,u ([I]gut/Ki,u) are 2.73 and 8.72 in HLMs and recombinant UGT1A1, respectively, indicating a high risk of intestinal DDI when dabrafenib was used in combination with irinotecan.

Conclusion

Dabrafenib is a potent noncompetitive inhibitor of UGT1A1 and may bring potential risk of DDI when combined with irinotecan.

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Authors and Affiliations

  1. School of Life and Pharmaceutical Sciences, Dalian University of Technology, 2 Dagong Road, Liaodongwan New District, Panjin, 124221, China

    Zhe Wang, Xiaoyu Wang, Zhen Wang, Xiaoyu Fan, Mingrui Yan, Lili Jiang, Yangliu Xia & Yong Liu

  2. Department of Occupational and Environmental Health, Dalian Medical University, No. 9 W. Lvshun South Road, Dalian, 116044, China

    Jun Cao

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  1. Zhe Wang
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Correspondence to Jun Cao or Yong Liu.

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This study was financially supported by the National Key Research and Development Program of China (2017YFC1702006), the Fundamental Research Funds for the Central Universities (DUT21LK11).

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ZW, JC, and YL contributed to the study conception and design. ZW, XW, and ZW contributed to the acquisition of data. XF and MY contributed to the analysis and interpretation of the data. ZW, LJ, and YX participated in the analysis and interpretation of the data and in the drafting of this article. All authors provided critical revision of the article for important intellectual content.

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Wang, Z., Wang, X., Wang, Z. et al. Prediction of Drug–Drug Interaction Between Dabrafenib and Irinotecan via UGT1A1-Mediated Glucuronidation. Eur J Drug Metab Pharmacokinet 47, 353–361 (2022). https://doi.org/10.1007/s13318-021-00740-x

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