Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2022-05-18 , DOI: 10.1016/j.biopha.2022.113136 Miklós Poór 1 , Hana Kaci 2 , Slávka Bodnárová 1 , Violetta Mohos 1 , Eszter Fliszár-Nyúl 1 , Sándor Kunsági-Máté 3 , Csilla Özvegy-Laczka 4 , Beáta Lemli 5
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Resveratrol (RES) is a widely-known natural polyphenol which is also contained by several dietary supplements. Large doses of RES can result in high micromolar levels of its sulfate and glucuronide conjugates in the circulation, due to the high presystemic metabolism of the parent polyphenol. Pharmacokinetic interactions of RES have been extensively studied, while only limited data are available regarding its metabolites. Therefore, in the current study, we examined the interactions of resveratrol-3-sulfate (R3S), resveratrol-3-glucuronide, and dihydroresveratrol (DHR; a metabolite produced by the colon microbiota) with human serum albumin (HSA), cytochrome P450 (CYP) enzymes, and organic anion transporting polypeptides (OATP) employing in vitro models. Our results demonstrated that R3S and R3G may play a major role in the RES-induced pharmacokinetic interactions: (1) R3S can strongly displace the site I marker warfarin from HSA; (2) R3G showed similarly strong inhibitory action on CYP3A4 to RES; (3) R3S proved to be similarly strong (OATP1B1/3) or even stronger (OATP1A2 and OATP2B1) inhibitor of OATPs tested than RES, while R3G and RES showed comparable inhibitory actions on OATP2B1.
中文翻译:
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白藜芦醇及其代谢物(resveratrol-3-sulfate、resveratrol-3-glucuronide 和 dihydroresveratrol)与血清白蛋白、细胞色素 P450 酶和 OATP 转运蛋白的相互作用
白藜芦醇 (RES) 是一种广为人知的天然多酚,也包含在多种膳食补充剂中。由于母体多酚的高系统前代谢,大剂量的 RES 可导致循环中高微摩尔水平的硫酸盐和葡糖苷酸结合物。RES 的药代动力学相互作用已被广泛研究,而关于其代谢物的数据有限。因此,在当前的研究中,我们检查了白藜芦醇-3-硫酸盐 (R3S)、白藜芦醇-3-葡糖苷酸和二氢白藜芦醇 (DHR;一种由结肠微生物群产生的代谢物) 与人血清白蛋白 (HSA)、细胞色素 P450 的相互作用。 (CYP) 酶和有机阴离子转运多肽 (OATP)在体外使用楷模。我们的研究结果表明,R3S 和 R3G 可能在 RES 诱导的药代动力学相互作用中起主要作用:(1)R3S 可以强烈取代 HSA 中的位点 I 标记华法林;(2) R3G对CYP3A4对RES表现出同样强的抑制作用;(3) 经证实,R3S 对 OATPs 的抑制作用与 RES 相似(OATP1B1/3)甚至更强(OATP1A2 和 OATP2B1),而 R3G 和 RES 对 OATP2B1 的抑制作用相当。