大黄酸和大黄素对大鼠体内马兜铃酸 I 及其去甲基代谢物药代动力学和组织分布的影响。
Effects of rhein and Rheum palmatum L. extract on the pharmacokinetics and tissue distribution of aristolochic acid I and its demethylated metabolite in rats.
机构信息
Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China; Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200080, China.
Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.
出版信息
J Ethnopharmacol. 2021 Mar 1;267:113537. doi: 10.1016/j.jep.2020.113537. Epub 2020 Nov 1.
ETHNOPHARMACOLOGICAL RELEVANCE
Aristolochic acid nephropathy (AAN) is a kidney disease caused by the administration of plants containing aristolochic acids (AAs). Aristolochic acid I (AAI) is the main toxic component in AAs. Organic anion transporters (OATs) 1 and 3 mediate the renal uptake of AAI, which is related to AAN. In our previous study, we found that anthraquinones derived from the herbal medicine Rheum palmatum L. (RP) inhibited both OAT1 and OAT3, with rhein exhibiting the greatest potency among the components.
AIM OF THE STUDY
This study aimed to investigate the effects of rhein and RP extract on the pharmacokinetics and tissue distribution of AAI and its demethylated metabolite (8-hydroxy-aristolochic acid I [AAIa]) in rats.
MATERIALS AND METHODS
Rhein and RP extract were used as OAT inhibitors, and AAI was used as the toxic substrate. The pharmacokinetics and tissue distribution of AAI and AAIa in rats following the intravenous injection of AAI (10 mg/kg) in the presence and absence of rhein (100 mg/kg) or RP extract (5 g crude drug/kg) were investigated.
RESULTS
Co-administration with rhein increased AUC of AAI and AAIa by 39 and 44%, respectively. However, the renal level of AAI was decreased to 50, 42, and 58% of those in rats treated with AAI alone at 5, 10, and 20 min after treatment, respectively, and the renal level of AAIa was decreased to 58, 57, and 61% of the level in rats treated with AAI alone, respectively, at these time points. In the RP extract co-administration group, AAI and AAIa plasma exposure was not significantly increased, but renal accumulation of AAI was decreased to 63, 58, and 68% of that in rats treated with AAI alone at 5, 10, and 20 min after treatment, respectively. In addition, renal accumulation of AAIa was decreased to 74, 70, and 70% of that in rats treated with AAI alone at 5, 10, and 20 min after treatment, respectively.
CONCLUSIONS
This study indicated that co-administration with rhein significantly increased the plasma exposure of AAI and AAIa while decreased their renal accumulation in rats. RP extract reduced the renal accumulation of AAI and AAIa, but have no significant effect on their plasma exposure levels in rats.
民族药理学相关性
马兜铃酸肾病（AAN）是一种由含马兜铃酸（AA）的植物引起的肾脏疾病。马兜铃酸 I（AAI）是 AA 中的主要毒性成分。有机阴离子转运蛋白（OAT）1 和 3 介导 AAI 的肾脏摄取，这与 AAN 有关。在我们之前的研究中，我们发现草药大黄（RP）中的蒽醌衍生物抑制了 OAT1 和 OAT3，其中大黄素的抑制作用最强。
研究目的
本研究旨在探讨大黄素和 RP 提取物对大鼠体内马兜铃酸和其去甲基代谢物（8-羟基马兜铃酸 I [AAIa]）药代动力学和组织分布的影响。
材料和方法
大黄素和 RP 提取物被用作 OAT 抑制剂，马兜铃酸被用作毒性底物。在静脉注射马兜铃酸（10mg/kg）的同时，给予大鼠大黄素（100mg/kg）或 RP 提取物（5g 生药/kg），研究马兜铃酸和 AAIa 在大鼠体内的药代动力学和组织分布。
结果
与大黄素合用使 AAI 和 AAIa 的 AUC 分别增加了 39%和 44%。然而，在治疗后 5、10 和 20 分钟，肾脏中马兜铃酸的水平分别降至单独给予马兜铃酸的 50%、42%和 58%，肾脏中 AAIa 的水平分别降至单独给予马兜铃酸的 58%、57%和 61%。在 RP 提取物合用组中，马兜铃酸和 AAIa 的血浆暴露量没有显著增加，但肾脏中马兜铃酸的蓄积量分别降至单独给予马兜铃酸的 63%、58%和 68%，在治疗后 5、10 和 20 分钟。此外，肾脏中 AAIa 的蓄积量分别降至单独给予马兜铃酸的 74%、70%和 70%，在治疗后 5、10 和 20 分钟。
结论
本研究表明，大黄素合用可显著增加大鼠体内马兜铃酸和 AAIa 的血浆暴露量，同时减少其肾脏蓄积。RP 提取物减少了马兜铃酸和 AAIa 的肾脏蓄积，但对其在大鼠体内的血浆暴露水平没有显著影响。
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