Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Drug Metab Dispos. 2013 May;41(5):958-65. doi: 10.1124/dmd.112.048272. Epub 2013 Feb 11.
Organic anion-transporting polypeptides (OATPs) are multispecific transporters mediating the uptake of endogenous compounds and xenobiotics in tissues that are important for drug absorption and elimination, including the intestine and liver. Silymarin is a popular herbal supplement often used by patients with chronic liver disease; higher oral doses than those customarily used (140 mg three times/day) are being evaluated clinically. The present study examined the effect of silymarin flavonolignans on OATP1B1-, OATP1B3-, and OATP2B1-mediated transport in cell lines stably expressing these transporters and in human hepatocytes. In overexpressing cell lines, OATP1B1- and OATP1B3-mediated estradiol-17β-glucuronide uptake and OATP2B1-mediated estrone-3-sulfate uptake were inhibited by most of the silymarin flavonolignans investigated. OATP1B1-, OATP1B3-, and OATP2B1-mediated substrate transport was inhibited efficiently by silymarin (IC₅₀ values of 1.3, 2.2 and 0.3 µM, respectively), silybin A (IC₅₀ values of 9.7, 2.7 and 4.5 µM, respectively), silybin B (IC₅₀ values of 8.5, 5.0 and 0.8 µM, respectively), and silychristin (IC₅₀ values of 9.0, 36.4, and 3.6 µM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 µM) significantly inhibited OATP-mediated estradiol-17β-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC₅₀ values indicated a low risk for silymarin-drug interactions in hepatic uptake with a customary silymarin dose. The extent of silymarin-drug interactions depends on OATP isoform specificity and concentrations of flavonolignans at the site of drug transport. Higher than customary doses of silymarin, or formulations with improved bioavailability, may increase the risk of flavonolignan interactions with OATP substrates in patients.
有机阴离子转运多肽 (OATPs) 是介导内源性化合物和外源性化合物摄取的多特异性转运体，在药物吸收和消除中发挥重要作用，包括肠道和肝脏。水飞蓟素是一种常用的草药补充剂，常用于慢性肝病患者；目前正在临床评估高于常规剂量（每天 3 次，每次 140 毫克）的水飞蓟素。本研究考察了水飞蓟素黄酮醇配基对稳定表达这些转运体的细胞系和人肝细胞中 OATP1B1、OATP1B3 和 OATP2B1 介导的转运的影响。在过表达细胞系中，大多数研究的水飞蓟素黄酮醇配基抑制了 OATP1B1 和 OATP1B3 介导的雌二醇-17β-葡糖苷酸摄取以及 OATP2B1 介导的雌酮-3-硫酸盐摄取。水飞蓟素（IC₅₀ 值分别为 1.3、2.2 和 0.3 μM）、水飞蓟宾 A（IC₅₀ 值分别为 9.7、2.7 和 4.5 μM）、水飞蓟宾 B（IC₅₀ 值分别为 8.5、5.0 和 0.8 μM）和水飞蓟素 C（IC₅₀ 值分别为 9.0、36.4 和 3.6 μM）有效地抑制了 OATP1B1、OATP1B3 和 OATP2B1 介导的底物转运。此外，水飞蓟素、水飞蓟宾 A 和水飞蓟宾 B（100 μM）显著抑制了 OATP 介导的雌二醇-17β-葡糖苷酸和瑞舒伐他汀在人肝细胞中的摄取。根据最大未结合门静脉浓度/IC₅₀ 值计算，在常规剂量下水飞蓟素与药物相互作用的肝摄取风险较低。水飞蓟素与药物相互作用的程度取决于 OATP 同工型特异性和药物转运部位的黄酮醇配基浓度。高于常规剂量的水飞蓟素或生物利用度改善的制剂可能会增加黄酮醇配基与 OATP 底物相互作用的风险，增加患者的风险。
