Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling.

Autor: Han DG; Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea., Seo SW; Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea., Choi E; Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea., Kim MS; Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea., Yoo JW; Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea., Jung Y; Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea., Yoon IS; Department of Manufacturing Pharmacy, College of Pharmacy and Research Institute for Drug Development, Pusan National University, Busan 46241, South Korea. Electronic address: insoo.yoon@pusan.ac.kr.
Jazyk: angličtina
Zdroj: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie [Biomed Pharmacother] 2022 Jul; Vol. 151, pp. 113141. Date of Electronic Publication: 2022 May 24.
DOI: 10.1016/j.biopha.2022.113141
Abstrakt: Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to its diverse pharmacological activities. Although there have been several preclinical and clinical investigations of resveratrol, the contributions of gut phase-II metabolism and enterohepatic circulation to the oral bioavailability and pharmacokinetics of resveratrol remain unclear. Furthermore, a physiologically-based pharmacokinetic (PBPK) model that accurately describes and predicts the systemic exposure profiles of resveratrol in clinical settings has not been developed. Experimental data were acquired from several perspectives, including in vitro protein binding and blood distribution, in vitro tissue S9 metabolism, in situ intestinal perfusion, and in vivo pharmacokinetics and excretion studies. Using these datasets, an in-house whole-body PBPK model incorporating route-dependent phase-II (glucuronidation and sulfation) gut metabolism and enterohepatic circulation processes was constructed and optimized for chemical-specific parameters. The developed PBPK model aligned with the observed systemic exposure profiles of resveratrol in single and multiple dosing regimens with an acceptable accuracy of 0.538-0.999-fold errors. Furthermore, the model simulations elucidated the substantial contribution of gut first-pass metabolism to the oral bioavailability of resveratrol and suggested differential effects of enterohepatic circulation on the systemic exposure of resveratrol between rats and humans. After partial modification and verification, our proposed PBPK model would be valuable to optimize dosage regimens and predict food-drug interactions with resveratrol-based natural products in various clinical scenarios.
(Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
Databáze: MEDLINE
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