Role of MRPs transporters in pharmacokinetics and intestinal toxicity of irinotecan.

Autor: Du T; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China., Luo T; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China., Wang J; Jiangxi Guhan Refined Chinese Herbal Pieces Co., Ltd., Nanchang, 330041, China., Sun R; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China; Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 4349 Martin Luther King Boulevard, Houston, TX, 77204, United States. Electronic address: Dutingsrj@gmaill.com., Cai H; Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China. Electronic address: nmdp65@163.com.
Jazyk: angličtina
Zdroj: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association [Food Chem Toxicol] 2023 Dec; Vol. 182, pp. 114171. Date of Electronic Publication: 2023 Nov 11.
DOI: 10.1016/j.fct.2023.114171
Abstrakt: To identify additional genetic markers contributing to variability in CPT-11 disposition and toxicity, we assessed impact of the multiple drug-resistant transporters 1, 2, and 3 (MRP1, MRP2, and MRP3) on the intestinal toxicity, pharmacokinetics, tissue distribution and biliary excretion of CPT-11 using a knockout mouse model. Mrp1/3 knockout had minor impact on intestinal toxicity of CPT-11, tissue distribution, biliary excretion, and PK parameter of its active metabolites SN38. Conversely, Mrp2 -/- mice, with low carboxylesterase activity, displayed insensitivity to CPT-11 toxicity due to reduced intestinal exposure to SN38. In PK studies, Mrp1/2 knockout significantly increased the AUC of CPT-11 compared to their AUC in FVB mice. However, the AUC of SN38 in Mrp2 -/- mice was decreased by 3.25-fold. Mrp3 knockout only slightly increased SN38 plasma exposure. Lastly, Mrp2/3 knockout increased biliary excretion amount of CPT-11 by 67.2% and 48.5% compared to wild-type mice, respectively. Consequently, Mrp1/3 deficiency didn't change SN38 tissue distribution. Finally, correlation analysis demonstrated that tissue exposure to SN38 was better correlated with toxicity than plasma AUC of SN38. Mrp1/2/3 deficiency showed a minor impact on PK, biliary excretion, distribution and intestinal exposure of SN38, and as a result, did not affect the intestinal toxicity of CPT-11.
Competing Interests: Declaration of competing interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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