Active Hydrophilic Components of the Medicinal HerbSalvia miltiorrhiza(Danshen) Potently Inhibit Organic Anion Transporters 1 (Slc22a6) and 3 (Slc22a8)

Abstract

Many active components of herbal products are small organic anions, and organic anion transporters were previously demonstrated to be a potential site of drug-drug interactions. In this study, we assessed the inhibitory effects of six hydrophilic components of the herbal medicine Danshen, lithospermic acid, protocatechuic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B, and tanshinol, on the function of the murine organic anion transporters, mOat1 and mOat3. All of Danshen components significantly inhibited mOat1- and mOat3-mediated substrate uptake (P < 0.001) with lithospermic acid (LSA), protocatechuic acid, rosmarinic acid (RMA), and salvianolic acid A (SAA) producing virtually complete inhibition under test conditions. Kinetic analysis demonstrated that LSA, RMA, and SAA were competitive inhibitors. As such, K i values were estimated as 14.9 ± 4.9 μM for LSA, 5.5 ± 2.2 μM for RMA, and 4.9 ± 2.2 μM for SAA on mOat1-mediated transport, and as 31.1 ± 7.0 μM for LSA, 4.3 ± 0.2 μM for RMA, and 21.3 ± 7.7 μM for SAA on mOat3-mediated transport. These data suggest that herb-drug interactions may occur in vivo on the human orthologs of these transporters in situations of polypharmacy involving Danshen and clinical therapeutics known to be organic anion transporter substrates.

Effect of luteolin and apigenin on rosmarinic acid bioavailability in Caco-2 cell monolayers

“…14 Recent studies show that rosmarinic acid is a competitive inhibitor of these transporters. 15 In light of these ndings, the present results suggest that rosmarinic acid may be transported by Oatp, which can be inhibited by competition with digoxin. The data also seem to indicate that the MCT is in fact involved in the transport of rosmarinic acid (competition with benzoic acid).…”

Interaction of Natural Dietary and Herbal Anionic Compounds and Flavonoids with Human Organic Anion Transporters 1 (SLC22A6), 3 (SLC22A8), and 4 (SLC22A11)

“…Estimated IC 50 values were 1.2 ± 0.4  μ M for 1,3-dicaffeoylquinic acid and 2.7 ± 0.2  μ M for 18 β -glycyrrhetinic acid. Numerous studies investigating the mode of inhibition produced on hOAT1 and hOAT3 for a broad array of compounds have demonstrated the interaction to be competitive [5, 18–22]. Therefore, assuming competitive inhibition of hOAT1, inhibition constants ( K i ) were estimated as 1.1 ± 0.2  μ M for 1,3-dicaffeoylquinic acid and 2.5 ± 0.2  μ M for 18 β -glycyrrhetinic acid.…”

“…Several dietary flavonoids and their metabolic conjugates (e.g., sulfates and glucuronides) were identified as potent inhibitors and/or substrates of human (h) OAT1, hOAT3, and hOAT4 [3, 4]. Phenolic acids, for example, contained in the widely used Chinese herbal medicine Danshen ( Salvia miltiorrhiza ) or common berries such as strawberries or blueberries, were similarly demonstrated to interact with these three transporters [5, 6]. These studies highlight the strong potential for hOAT-mediated natural product-drug interaction and the need to investigate further anionic compounds and flavonoids that are found in popular complementary/alternative medicines and natural supplements.…”

Interactions of 172 plant extracts with human organic anion transporter 1 (SLC22A6) and 3 (SLC22A8): a study on herb-drug interactions

“…OAT1 and OAT3 have been identified as the targets for potential HDIs. For example, components in the herbal medicine Salviae miltiorrhizae Radix et Rhizoma including lithospermic acid, rosmarinic acid, salvianolic acid A, salvianolic acid B and tanshinol have been shown to inhibit human OAT1 and OAT3 ( Wang & Sweet, 2012 ). The anthraquinones in rhubarb have been identified as strong inhibitors to human OAT1 and OAT3 ( Ma et al, 2014 ).…”