Hepatic organic anion transporting polypeptides mediate disposition of milk thistle flavonolignans and pharmacokinetic silymarin-drug interactions.
Hepatic organic anion transporting polypeptides mediate disposition of milk thistle flavonolignans and pharmacokinetic silymarin-drug interactions.
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肝脏有机阴离子转运多肽介导奶蓟黄酮木脂体的处置和药物动力学水飞蓟素-药物相互作用。
DOI：
10.1002/ptr.7049
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发表时间：
2021-06
期刊：
影响因子：
--
通讯作者：
Clarke JD
中科院分区：
文献类型：
--
作者：
Lynch KD;Montonye ML;Tian DD;Arman T;Oyanna VO;Bechtold BJ;Graf TN;Oberlies NH;Paine MF;Clarke JD
水飞蓟（L.）Gaertn。（Asteraceae），俗称水飞蓟，是一种植物性天然产品，用于自我治疗多种疾病，如2型糖尿病和非酒精性脂肪性肝炎（NASH）。水飞蓟种子（瘦果）的提取物，称为水飞蓟素，主要由几种黄酮木脂素组成。这些黄酮木质素的全身浓度可以影响水飞蓟素的潜在生物学效应和水飞蓟素-药物相互作用的药代动力学风险。本研究的目的是确定有机阴离子转运多肽（OATPs/ OATPs）在水飞蓟素黄酮木脂素配置和水飞蓟素-药物相互作用中的作用。测定水飞蓟素中7种主要黄酮木脂素为OATP1B1、OATP1B3和OATP2B1的底物。实验采用对照饮食和诱导nash饮食两种方式，分别给予匹伐他汀（OATP/ OATP探针底物）和水飞蓟素灌胃。在NASH动物中，Oatp1b2和Oatp1a4蛋白表达的降低增加了血浆浓度-时间曲线（AUC）下黄酮木脂素面积和最大血浆浓度。水飞蓟素抑制OATPs/ OATPs和nash相关的Oatp表达降低的联合作用导致动物血浆匹伐他汀AUC的增加。这些数据表明，OATPs/ OATPs有助于黄酮木质素的细胞摄取，并介导水飞蓟素和NASH对匹伐他汀全身暴露的相互作用。
Silybum marianum (L.) Gaertn. (Asteraceae), commonly known as milk thistle, is a botanical natural product used to self-treat multiple diseases such as type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH). An extract from milk thistle seeds (achenes), termed silymarin, is comprised primarily of several flavonolignans. Systemic concentrations of these flavonolignans can influence the potential biologic effects of silymarin and the risk for pharmacokinetic silymarin-drug interactions. The aims of this research were to determine the roles of organic anion transporting polypeptides (OATPs/Oatps) in silymarin flavonolignan disposition and in pharmacokinetic silymarin-drug interactions. The seven major flavonolignans from silymarin were determined to be substrates for OATP1B1, OATP1B3, and OATP2B1. Sprague Dawley rats were fed either a control diet or a NASH-inducing diet and administered pitavastatin (OATP/Oatp probe substrate), followed by silymarin via oral gavage. Decreased protein expression of Oatp1b2 and Oatp1a4 in NASH animals increased flavonolignan area under the plasma concentration-time curve (AUC) and maximum plasma concentration. The combination of silymarin inhibition of OATPs/Oatps and NASH-associated decrease in Oatp expression caused an additive increase in plasma pitavastatin AUC in the animals. These data indicate that OATPs/Oatps contribute to flavonolignan cellular uptake and mediate the interaction between silymarin and NASH on pitavastatin systemic exposure.
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