Inhibition of UGT1A1*1 and UGT1A1*6 catalyzed glucuronidation of SN-38 by silybins

  • Chem Biol Interact. 2022 Dec 1:368:110248. doi: 10.1016/j.cbi.2022.110248.
Wei Li  1 ,  Yin-Nan Chen  2 ,  Yue-Yue Chen  2 ,  Zhe Wang  3 ,  Zhen Wang  3 ,  Li-Li Jiang  3 ,  Hong-Can Shi  4 ,  Yong Liu  5
Affiliations
  • 1. Translational Medicine Research Institute, College of Medicine, Yangzhou University, Yangzhou, 225001, China; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, China.
  • 2. Translational Medicine Research Institute, College of Medicine, Yangzhou University, Yangzhou, 225001, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, China.
  • 3. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 124221, China.
  • 4. Translational Medicine Research Institute, College of Medicine, Yangzhou University, Yangzhou, 225001, China; Jiangsu Key Laboratory of Integrated Traditional Chinese and Western Medicine for Prevention and Treatment of Senile Diseases, Yangzhou University, Yangzhou, 225001, China. Electronic address: [email protected].
  • 5. School of Life and Pharmaceutical Sciences, Dalian University of Technology, Panjin, 124221, China. Electronic address: [email protected].
PMID: 36343684 DOI: 10.1016/j.cbi.2022.110248
Abstract

UGT1A1 is the main enzyme that catalyzes the metabolic elimination and detoxification of SN-38, the active form of the drug irinotecan. Milk thistle products have been used widely to protect the liver from injury associated with the use of chemotherapeutic agents. To evaluate whether SN-38 metabolism can be affected by milk thistle products, the inhibitory effects of silybins on UGT1A1*1 and UGT1A1*6 were evaluated in the present investigation. Both silybin A and silybin B potently inhibited SN-38 glucuronidation catalyzed by UGT1A1*1 or UGT1A1*6. It was noteworthy that silybin A and silybin B showed synergistic effect in UGT1A1*1 microsomes at concentration around IC50, while additive effect in UGT1A1*6. According to the predicted AUCi/AUC ratios (the ratio of the area under the plasma concentration-time curve of SN-38 in the presence and absence of silybins), the coadministration of irinotecan and several milk thistle products, including silybin-phosphatidylcholine complex, two Legalon capsules, four Silymarin tablets or four Liverman capsules, may lead to clinically significant herb-drug interactions (HDI) via UGT1A1 inhibition. Meanwhile, Rgut values were much higher than 11 in all the groups, indicating potential HDI due to intestinal UGT1A1 inhibition.

Keywords
Herb-drug interaction (HDI); SN-38; Silybins; UGT1A1*1; UGT1A1*6.
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