Potential Risk of Food-Drug Interactions: Citrus Polymethoxyflavones and Flavanones as Inhibitors of the Organic Anion Transporting Polypeptides (OATP) 1B1, 1B3, and 2B1

Abstract

Background and Objectives Citrus flavonoids are not only components of daily nutrition, they are also promoted as dietary supplements and are important ingredients in traditional medicines. Interactions of flavonoids with synthetic drugs represent an often neglected issue. We therefore investigated in vitro whether the polymethoxyflavones nobiletin, sinensetin, and tangeretin and the flavonoid rutinosides didymin, hesperidin, and narirutin can inhibit human organic anion transporting polypeptides (OATP) 1B1, 1B3, and 2B1, which are important transporters mediating drug-drug and food-drug interactions. Methods Inhibition was investigated by quantifying the decreased uptake of the fluorescent OATP1B1 and OATP1B3 substrate 8-fluorescein-cAMP in HEK293 cells overexpressing OATP1B1 or OATP1B3 and of the fluorescent OATP2B1 substrate 4′,5′-dibromofluorescein in HEK293 cells overexpressing OATP2B1. Results We demonstrate that all flavonoids investigated inhibit OATP2B1 in the lower micromolar range (IC 50 between 1.6 and 14.2 µM), but only the polymethoxyflavones also inhibit OATP1B1 and 1B3 (IC 50 between 2.1 and 21 µM). Conclusions All flavonoids investigated might contribute to the intestinal OATP2B1-based interactions with drugs observed with citrus juices or fruits. In contrast, the concentration of the polymethoxyflavones after consumption of citrus juices or fruits is most likely too low to reach relevant systemic concentrations and thus to inhibit hepatic OATP1B1 and OATP1B3, but there might be a risk when they are consumed as medicines or as dietary supplements.

Citrus Fruit-Derived Flavanone Glycoside Narirutin is a Novel Potent Inhibitor of Organic Anion-Transporting Polypeptides

“…13,19,20 Recently, Bajraktari-Sylejmani et al have shown that narirutin inhibits OATP2B1-mediated 4′,5′-dibromofluorescein transport. 29 However, they did not analyze the inhibitory kinetics of narirutin in detail. In addition, it has not been reported to have inhibitory effects on OATP1A2.…”

Low risk of the TMPRSS2 inhibitor camostat mesylate and its metabolite GBPA to act as perpetrators of drug-drug interactions

“…Although the small effect on OATP1B1 is most likely not relevant in vivo , because systemic concentrations of GBPA are too low for inhibition of this liver-specific uptake transporter, the potency for intestinal OATP2B1 inhibition is clearly high enough to be of clinical relevance. Inhibition of this uptake transporter represents a typical feature of several citrus flavonoids [ [38] , [39] , [40] ] and can lead to decreased bioavailability of respective substrates as already postulated e.g. for aliskiren [ 41 , 42 ], celiprolol [ 43 ], and rosuvastatin [ 44 ].…”

Potential herb–drug interactions between anti-COVID-19 drugs and traditional Chinese medicine

“…Hesperidin and its metabolite hesperetin showed an inhibitory effect on the activities of CYP1A, CYP1B1, CYP3A4, and P-gp 259 , 260 . Tangeretin exerts an inhibitive effect on OATP2B1 261 , but can significantly increase the mRNA expression of CYP3A4 by regulating PXR 262 . Nobiletin is both a CYP1A2 inhibitor and inducer, while tangeretin is an inducer of CYP3A4 263 .…”