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

Abstract

Active components of complementary/alternative medicines and natural supplements are often anionic compounds and flavonoids. As such, organic anion transporters (OATs) may play a key role in their pharmacokinetic and pharmacological profiles, and represent sites for adverse drug-drug interactions. Therefore, we assessed the inhibitory effects of nine natural products, including flavonoids (catechin and epicatechin), chlorogenic acids (1,3- and 1,5-dicaffeoylquinic acid), phenolic acids (ginkgolic acids (13 : 0), (15 : 1), and (17 : 1)), and the organic acids ursolic acid and 18β-glycyrrhetinic acid, on the transport activity of the human OATs, hOAT1 (SLC22A6), hOAT3 (SLC22A8), and hOAT4 (SLC22A11). Four compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acid (17 : 1), and 18β-glycyrrhetinic acid, significantly inhibited hOAT1-mediated transport (50 μM inhibitor versus 1 μM substrate). Five compounds, 1,3- and 1,5-dicaffeoylquinic acid, ginkgolic acids (15 : 1) and (17 : 1), and epicatechin, significantly inhibited hOAT3 transport under similar conditions. Only catechin inhibited hOAT4. Dose-dependency studies were conducted for 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid on hOAT1, and IC50 values were estimated as 1.2 ± 0.4 μM and 2.7 ± 0.2 μM, respectively. These data suggest that 1,3-dicaffeoylquinic acid and 18β-glycyrrhetinic acid may cause significant hOAT1-mediated DDIs in vivo; potential should be considered for safety issues during use and in future drug development.

Flavonoids Are Inhibitors of Human Organic Anion Transporter 1 (OAT1)–Mediated Transport

“…In addition, flavonoids have been found to have modulatory effects on several efflux transporters (Morris and Zhang, 2006) and a few uptake transporters, such as OATP1B1 (Wang et al, 2005) and MCT1 (Wang and Morris, 2007). Regarding the interaction between flavonoids and OAT1, there is only limited information available in the literature (Hong et al, 2007;Wang and Sweet, 2013a).…”

“…In addition, the active components of a few medicinal herbs, including Salvia miltiorrhiza (Danshen) and Rheum sp., have also been found to potently interfere with OAT-mediated renal elimination (Wang and Sweet, 2012a;Wang et al, 2013). The interactions between OAT1 and flavonoids, a class of polyphenolic compounds with exceptional safety records, have also been evaluated, and a few flavonoids have been found to be potent OAT1 inhibitors in vitro (Hong et al, 2007;Wang and Sweet, 2013a). At this time, only a limited number of flavonoids have been examined.…”

Beneficial Pharmacokinetic Drug Interactions: A Tool to Improve the Bioavailability of Poorly Permeable Drugs

“…One family of the SLC superfamily with clinical relevance is the OAT uptake transporters expressed mainly in the renal proximal tubules encoded specifically by four of the SLCO gene families [ 7 , 13 , 14 , 15 ]. OAT1 and OAT3 are situated on the basolateral side of the membrane and are responsible for excretion of compounds by tubular secretion of metabolites and/or other xenobiotics from the blood to the urine ( Figure 1 C).…”

“…OAT1 and OAT3 are situated on the basolateral side of the membrane and are responsible for excretion of compounds by tubular secretion of metabolites and/or other xenobiotics from the blood to the urine ( Figure 1 C). In contrast, OAT4 is situated on the apical side of the membrane where it is responsible for re-absorbing anionic compounds from the urine to the blood [ 13 , 15 ]. Since certain drugs are mainly excreted via the kidneys, the OATs play a role in the reduction of plasma levels of such drugs via excretion.…”

“…Concurrent use of different remedies poses a potential risk for patients, especially with herb-drug interactions being capable of modulating pharmacodynamic and pharmacokinetic profiles of drugs [ 2 , 37 , 38 ]. Well known herb-drug interactions have been thoroughly described in the literature and includes interactions such as St John’s wort’s induction of P-gp expression and metabolism [ 2 , 30 ], UGT inhibition by milk thistle, saw palmetto and cranberry [ 23 ] and Gingko biloba ’s pharmacodynamic brain protective properties [ 15 ]. Recently explored possible beneficial pharmacokinetic interactions regarding commonly used herbs are described in the following sections.…”