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

Abstract

Context: Organic anion-transporting polypeptide 2B1 (OATP2B1) which is highly expressed in enterocytes and hepatocytes could be a key determinant for the intestinal absorption and hepatic uptake of its substrate drugs. Natural products are commonly used in traditional Chinese medicine, foods, and beverages. Objective: The objective of this study is to determine the OATP2B1-mediated drug interactions that could occur between natural products and OATP2B1 substrate drugs. Materials and methods: Human OATP2B1 was transiently expressed in human embryonic kidney (HEK293) cells and characterized by immunofluorescence, Western blot, and uptake assay. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods for detecting OATP2B1 substrates estrone-3-sulfate (E3S) and three statins had been developed and were employed to investigate the effects of 27 frequently used natural products on the function of OATP2B1. Uptake of 5 lM E3S and 1 lM statins in the absence or presence of natural products was measured at 37 C for 2 min with empty vector-and OATP2B1-transfected HEK293 cells. The IC 50 values of inhibitors for OATP2B1-mediated 5 lM E3S uptake were determined. Results: Our results showed that mulberrin, scutellarin, quercetin, and glycyrrhetinic acid were strong inhibitors of OATP2B1-mediate E3S uptake with IC 50 values being 1.8, 2.0, 7.5, and 13.0 lM, which were comparable with their plasma concentrations in clinical trials. They also inhibited OATP-mediated uptake of atorvastatin, fluvastatin, and rosuvastatin. These results indicated that clinically relevant drug interactions could occur between these natural compounds and OATP2B1 substrate drugs. Discussion and conclusion: The information obtained from this study might be helpful to predict and to avoid potential OATP2B1-mediated drug interactions.

Intestinal Drug Interactions Mediated by OATPs: A Systematic Review of Preclinical and Clinical Findings

“…Additionally, some constituents that are not listed in these tables such as (-)-catechin, chlorogenic acid, (-)-epicatechin, (-)-epigallocatechin, (-)-epigallocatechin gallate, kaempferol, naringenin, and phlorhizin showed moderate-to-weak inhibition of these transporters. 30,32,96,192,[194][195][196] Taken together, these in vitro findings confirm the ability of these natural products to inhibit intestinal OATPs. Indeed, among the 9 inhibitors identified in the clinical DDI studies (Table 4), apple juice, grapefruit juice, green tea, and orange juice all exhibited potent inhibition in vivo, reducing the exposure of co-administered victim drugs by up to 85%.…”

Effects of berberine on the pharmacokinetics of losartan and its metabolite EXP3174 in rats and its mechanism

“…For example, the antifungal ketoconazole, a potent inhibitor of CYP3A4, causes drug-drug interactions with drugs that are substrates of CYP3A4 (Xiaoyang et al 2015). However, undesired drug-drug interactions can also be caused by transporters (Kim et al 1998;Li et al 2014;Joyce et al 2015;Wen et al 2016). Some drug interactions, previously believed to be P450-mediated, are now considered at least in part due to the inhibition of transport proteins.…”

The involvement of human organic anion transporting polypeptides (OATPs) in drug-herb/food interactions

“…The flavonoid scutellarin is enriched in breviscapine. Extracts from these natural sources have been found to impair the transport function of OATPs in the over-expressing cells [ 67 , 72 , 76 ]. Horny Goat Weed is a widely used Chinese medicine in Asian countries.…”

“…For instance, licorice contains the saponin glycyrrhizic acid, which has been in managing chronic hepatitis and gastric ulcers. Glycyrrhizic acid was reported to inhibit the cellular uptake of OATP substrates atorvastatin, fluvastatin and rosuvastatin [ 76 ]. Literature also indicated that chemically similar molecules like the triterpenoid saponins ursolic acid, oleanolic acid and betulinic acid, are potent OATP inhibitors [ 64 , 68 ].…”