Interaction of Silymarin Flavonolignans with Organic Anion-Transporting Polypeptides

Abstract

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-17b-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 (IC 50 values of 1.3, 2.2 and 0.3 mM, respectively), silybin A (IC 50 values of 9.7, 2.7 and 4.5 mM, respectively), silybin B (IC 50 values of 8.5, 5.0 and 0.8 mM, respectively), and silychristin (IC 50 values of 9.0, 36.4, and 3.6 mM, respectively). Furthermore, silymarin, silybin A, and silybin B (100 mM) significantly inhibited OATP-mediated estradiol-17b-glucuronide and rosuvastatin uptake into human hepatocytes. Calculation of the maximal unbound portal vein concentrations/IC 50 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.

Hepatocellular Organic Anion–Transporting Polypeptides (OATPs) and Multidrug Resistance–Associated Protein 2 (MRP2) Are Inhibited by Silibinin

“…While this manuscript was in revision, Köck et al (2013) reported inhibition of OATP1B1, OATP1B3, and OATP2B1 transport function by silibinin A and B, which is in accordance with our findings.…”

Identification of natural products as modulators of OATP2B1 using LC-MS/MS to quantify OATP-mediated uptake

“…Inhibition or stimulation of OATP2B1's function by drugs or foods could alter the pharmacokinetics of OATP2B1 substrates and potentially lead to adverse effects. Quite a few interactions between OATP2B1 and natural products have been reported in the literature (Fuchikami et al, 2006;Imanaga et al, 2011;Kock et al, 2013;Li et al, 2014;Mandery et al, 2010;Satoh et al, 2005;Shirasaka et al, 2013a,b;Tapaninen et al, 2010Tapaninen et al, , 2011Roth et al, 2011), suggesting that OATP2B1 could interact with a wide range of natural products. To identify more OATP2B1 modulators from natural products and to avoid potential adverse drug-drug and drug-food interactions, in this work the effects of 27 natural compounds and extracts on the function of OATP2B1 have been investigated.…”

“…Roth et al (2011) reported that green tea catechins epicatechin gallate and epigallocatechin gallate significantly inhibited OATP2B1-mediated E3S uptake. Several flavonoids, silymarin flavonolignans, and antidiabetic drugs have also been reported to inhibit OATP2B1 in vitro (Bachmakov et al, 2008;Klatt et al, 2013;Kock et al, 2013;Li et al, 2014;Mandery et al, 2010). These reports demonstrated that OATP2B1 could interact with a wide range of natural products.…”

Milk Thistle Constituents Inhibit Raloxifene Intestinal Glucuronidation: A Potential Clinically Relevant Natural Product–Drug Interaction

“…Silybin A 59 6 6.1 56 6 5.1 5.0 6 0.65 4.2 6 0.48 40 6 6.8 67 6 12 79 6 7.9 72 6 7.7 Silybin B 66 6 6.0 31 6 3.2 3.3 6 0.39 2.8 6 0.34 47 6 13 19 6 3.4 74 6 8.6 65 6 7.6 Silibinin 33 6 3.2 27 6 2.9 3.2 6 0.33 2.8 6 0.25 50 6 7.7 39 6 4.0 120 6 19 86 6 12 Silymarin 28 6 3.1 27 6 2.7 8.3 6 1.1 6.7 6 0.85 73 6 18 30 6 5.4 91 6 14 81 6 12 dmd.aspetjournals.org 3-fold, supporting these constituents as marker constituents predictive of the complex mixtures. Transport proteins, including organic anion-transporting polypeptides (OATPs), multidrug resistance proteins, and P-glycoprotein (P-gp) have been reported to contribute to the disposition of raloxifene, R4G, R6G (Jeong et al, 2004(Jeong et al, , 2005aChang et al, 2006;Trdan Lu sin et al, 2012a, b), and milk thistle flavonolignans (Miranda et al, 2008;Köck et al, 2013;Wlcek et al, 2013). The risk of interactions via milk thistle flavonolignan inhibition of OATP1B1-and OATP1B3-mediated hepatic uptake is believed to be low, based on limited systemic exposure (Köck et al, 2013).…”

“…Transport proteins, including organic anion-transporting polypeptides (OATPs), multidrug resistance proteins, and P-glycoprotein (P-gp) have been reported to contribute to the disposition of raloxifene, R4G, R6G (Jeong et al, 2004(Jeong et al, , 2005aChang et al, 2006;Trdan Lu sin et al, 2012a, b), and milk thistle flavonolignans (Miranda et al, 2008;Köck et al, 2013;Wlcek et al, 2013). The risk of interactions via milk thistle flavonolignan inhibition of OATP1B1-and OATP1B3-mediated hepatic uptake is believed to be low, based on limited systemic exposure (Köck et al, 2013). Similarly, silibinin may inhibit multidrug resistance protein 2-mediated canalicular efflux of raloxifene and its conjugates, but hepatocellular concentrations are likely too low to elicit clinically meaningful effects (Wlcek et al, 2013).…”