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

Abstract

Organic anion-transporting polypeptides (OATPs) 1A2 and OATP2B1 are expressed in the small intestine and are involved in drug absorption. We identified narirutin, which is present in grapefruit juice, as a novel OATP inhibitor. The citrus fruit jabara also contains high levels of narirutin; therefore, we investigated the inhibitory potency of jabara juice against OATPs. The inhibitory effects of various related compounds on the transport activity of OATPs were evaluated using OATP-expressing HEK293 cells. The IC50 values of narirutin for OATP1A2- and OATP2B1-mediated transport were 22.6 and 18.2 μM, respectively. Other flavanone derivatives from grapefruit juice also inhibited OATP1A2/OATP2B1-mediated transport (order of inhibitory potency: naringenin > narirutin > naringin). Five percent jabara juice significantly inhibited OATP1A2- and OATP2B1-mediated transport by 67 ± 11 and 81 ± 5.5%, respectively (p < 0.05). Based on their inhibitory potency and levels in grapefruit juice, the inhibition of OATPs by grapefruit juice is attributable to both naringin and narirutin. Citrus × jabara, which contains narirutin, potently inhibits OATP-mediated transport.

Exposure of Fexofenadine, but Not Pseudoephedrine, Is Markedly Decreased by Green Tea Extract in Healthy Volunteers

“…Moreover, OATP1A2‐mediated fexofenadine uptake was nearly completely inhibited in the presence of EGCG (100 μM and 1 mM) or GTE (0.1 and 1 mg/mL; P < 0.01; Figure ). On the other hand, only slight but significant uptake of fexofenadine (10 μM) mediated by OATP2B1 was observed in HEK‐OATP2B1 cells compared with vector control cells at both pH 6.3 and pH 7.3 ( Figure ), which is in accordance with recent papers 29,30 . However, due to low uptake ratio for OATP2B1‐mediated fexofenadine transport, inhibition studies at both pH conditions revealed no consistent effect for both EGCG and GTE (data not shown).…”

“…This was confirmed in BSP transport assay for OATP2B1 ( Figure ). On the other hand, only slight uptake of fexofenadine was observed in HEK‐OATP2B1 cells at pH 6.3 and pH 7.3, which is in accordance with recently published data 29,30,41 . Due to low uptake ratio (HEK‐OATP2B1/HEK‐Co), we found no consistent effects of GTE and EGCG on OATP2B1‐mediated fexofenadine transport.…”

“…On the other hand, only slight uptake of fexofenadine was observed in HEK-OATP2B1 cells at pH 6.3 and pH 7.3, which is in accordance with recently published data. 29,30,41 Due to low uptake ratio (HEK-OATP2B1/ HEK-Co), we found no consistent effects of GTE and EGCG on OATP2B1-mediated fexofenadine transport. As mentioned above, the subjects orally ingested the GTE aqueous solution containing ~ 4.4 mM of EGCG, and therefore the concentration of EGCG in the gastrointestinal tract may be sufficient to inhibit the uptake transport of fexofenadine by OATP1A2 into enterocytes, which may lead to a reduction in the oral bioavailability.…”

“…On the other hand, only slight but significant uptake of fexofenadine (10 μM) mediated by OATP2B1 was observed in HEK-OATP2B1 cells compared with vector control cells at both pH 6.3 and pH 7.3 (Figure S3), which is in accordance with recent papers. 29,30 However, due to low uptake ratio for OATP2B1-mediated fexofenadine transport, inhibition studies at both pH conditions revealed no consistent effect for both EGCG and GTE (data not shown). We used BSP as a typical substrate of OATP2B1, and found that EGCG (100 μM and 1 mM) and GTE (0.1 and 1 mg/mL) significantly reduced OATP2B1-mediated uptake of BSP at both pH 6.3 and pH 7.3 (P < 0.01; Figure 5b,c).…”

Inhibitory Effects of Cranberry Juice and Its Components on Intestinal OATP1A2 and OATP2B1: Identification of Avicularin as a Novel Inhibitor

“…Moreover, jabara (Citrus jabara) juice was found to contain considerable levels of narirutin but not naringin. 23 However, the inhibitory effects of other fruit juices on OATPs have yet to be determined, and certain juices may cause drug interactions with OATP substrates via OATP inhibition. Therefore, it is clinically important to comprehensively assess the inhibitory effects of various fruit juices on OATPs.…”