Flavonoids as a Novel Class of Human Organic Anion-Transporting Polypeptide Oatp1b1 (Oatp-C) Modulators

Wang, Xiaodong; Wolkoff, Allan W.; Morris, Marilyn E.

doi:10.1124/dmd.105.005926

Cited by 139 publications

(116 citation statements)

References 37 publications

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“…3). Likewise, although a previous study found that EGC inhibited OATP1B1-mediated uptake of dehydroepiandrosterone sulfate (Wang et al, 2005), we did not see significant inhibition of OATP1B1-mediated uptake of estrone-3-sulfate in the presence of EGC. Thus, we propose that for OATP1B1 and OATP1B3, the effect of potential inhibitors should always be tested by using several substrates instead of a single prototypical substrate.…”

Section: Effect Of Green Tea Catechins On Oatp Functioncontrasting

confidence: 49%

“…Because of the many apparent health benefits of green tea and EGCG, green tea beverages and extract supplements are widely used, creating an increased risk of adverse interactions. EGC and EGCG have been shown to inhibit OATP1B1-mediated uptake of dehydroepiandrosterone sulfate (Wang et al, 2005), whereas all four catechins inhibited estrone-3-sulfate uptake mediated by OATP2B1 (Fuchikami et al, 2006). However, the effect of catechins on the function of OATP1A2 and OATP1B3 has not been reported, and it is not known whether any of these four catechins are transported by any of the OATPs.…”

Section: Introductionmentioning

confidence: 81%

“…Thus, inhibition or stimulation of OATP function by food or dietary supplements can alter the pharmacokinetics of OATP substrates and potentially lead to adverse effects. Recent studies have indicated that flavonoids found in fruit juices, in green tea, and in many dietary supplements can alter the function of OATP1A2, OATP1B1, and OATP2B1 (Wang et al, 2005;Fuchikami et al, 2006;Bailey et al, 2007). Such interactions can affect the bioavailability of drugs such as fexofenadine and celiprolol, known OATP substrates (Greenblatt, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Interactions of Green Tea Catechins with Organic Anion-Transporting Polypeptides

Roth¹,

Timmermann²,

Hagenbuch³

2011

Drug Metab Dispos

172

160

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ABSTRACT:Organic anion-transporting polypeptides (OATPs) are multispecific transporters that mediate the uptake of numerous drugs and xenobiotics into cells. Here, we examined the effect of green tea (Camellia sinensis) catechins on the function of the four OATPs expressed in human enterocytes and hepatocytes. Uptake of the model substrate estrone-3-sulfate by cells expressing OATP1A2, OATP1B1, OATP1B3, or OATP2B1 was measured in the absence and presence of the four most abundant flavonols found in green tea. Uptake by OATP1A2, OATP1B1, and OATP2B1 was inhibited by epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) in a concentration-dependent way. In contrast, OATP1B3-mediated uptake of estrone-3-sulfate was strongly stimulated by EGCG at low substrate concentrations. The effect of EGCG on OATP1B3 was also studied with additional substrates: uptake of estradiol-17␤-glucuronide was unchanged, whereas uptake of Fluo-3 was noncompetitively inhibited. Both ECG and EGCG were found to be substrates of OATP1A2 (K m values of 10.4 and 18.8 M, respectively) and OATP1B3 (34.1 and 13.2 M, respectively) but not of OATP1B1 or OATP2B1. These results indicate that two of the major flavonols found in green tea have a substantial effect on the function of OATPs expressed in enterocytes and hepatocytes and can potentially alter the pharmacokinetics of drugs and other OATP substrates. In addition, the diverse effects of EGCG on the transport of other OATP1B3 substrates suggest that different transport/ binding sites are involved.

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Section: Effect Of Green Tea Catechins On Oatp Functioncontrasting

confidence: 49%

Section: Introductionmentioning

confidence: 81%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Interactions of Green Tea Catechins with Organic Anion-Transporting Polypeptides

Roth¹,

Timmermann²,

Hagenbuch³

2011

Drug Metab Dispos

172

160

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“…It was surprising to discover that an increase of the BG concentration from 10 to 100 μM did not proportionally increase the inhibition effect on the uptake of Fluo3 by OATP 1B3, which could be due to the partial competitive inhibition effect of BG on OATP 1B3. A previous study by Wang et al (23) showed interactions between OATP 1B1 and a series of flavonoid aglycones. In the present study, we demonstrated in both in vitro and in vivo systems that flavonoid conjugate metabolites are also likely eliminated in the liver through OATPs.…”

Section: −1mentioning

confidence: 99%

Hepatic Metabolism and Disposition of Baicalein via the Coupling of Conjugation Enzymes and Transporters—In Vitro and In Vivo Evidences

Zhang

Lin

et al. 2011

AAPS J

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Abstract. Baicalein (Ba) was found to be subject to serious first-pass metabolism after oral administration. We previously revealed the important role of intestine in the low oral bioavailability of Ba. The present study aims to evaluate the hepatic metabolism and disposition of Ba. Ba was given to Sprague-Dawley rats through bolus or infusion via intravenous or intra-portal route of administrations. Both plasma and bile samples at different time intervals were obtained. Concentrations of Ba and potential metabolites in the collected samples were analyzed with HPLC/UV and identified by LC/MS/ MS, respectively. Plasma concentration versus time profiles of Ba obtained from intravenous and intraportal administrations were compared to estimate the extent of hepatic metabolism. In addition, transport studies of baicalein-7-glucuronide (BG), one of the major metabolites of Ba, were carried out using transfected cell systems overexpressing various human organic anion-transporting polypeptide (OATP) isoforms to estimate the specific transporters involved in the hepatic disposition of Ba metabolites. The results showed that liver, in addition to intestine, also conferred extensive metabolism to Ba. Several mono-and di-conjugates of Ba, which were mainly glucuronides, sulfates, and methylates, were found in bile. The transport study demonstrated that besides MRPs and BCRP, human OATP2B1 and OATP1B3 in liver might also mediate the secretion of BG to bile. In summary, liver plays an important role in the metabolism of Ba and transport of its conjugated metabolites.

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“…It is noteworthy that although compound 6 stimulated transport of estrone-3-sulfate, the structurally similar rutin (compound 5) did not show this effect. However, rutin was previously shown to stimulate uptake of 0.5 M dehydroepiandrosterone sulfate by OATP1B1 (Wang et al, 2005). This demonstrates that stimulation of uptake is not a phenomenon specific to OATP1B3, but may be shared by all OATPs.…”

mentioning

confidence: 78%

Isolation of Modulators of the Liver-Specific Organic Anion-Transporting Polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae)

Roth¹,

Araya²,

Timmermann³

et al. 2011

J Pharmacol Exp Ther

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Organic anion-transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3) are liver-specific transporters that mediate the uptake of a broad range of drugs into hepatocytes, including statins, antibiotics, and many anticancer drugs. Compounds that alter transport by one or both of these OATPs could potentially be used to target drugs to hepatocytes or improve the bioavailability of drugs that are cleared by the liver. In this study, we applied a bioassay-guided isolation approach to identify such compounds from the organic extract of Rollinia emarginata Schlecht (Annonaceae). Fractions of the plant extract were screened for effects on OATP1B1-and OATP1B3-mediated transport of the model substrates estradiol-17␤-glucuronide and estrone-3-sulfate. We isolated three compounds, ursolic acid, oleanolic acid, and 8-transp-coumaroyloxy-␣-terpineol, which inhibited estradiol-17␤-glucuronide uptake by OATP1B1 but not OATP1B3. In addition, a rare compound, quercetin 3-O-␣-L-arabinopyranosyl(132) ␣-Lrhamnopyranoside, was identified that had distinct effects on each OATP. OATP1B1 was strongly inhibited, as was OATP1B3-mediated transport of estradiol-17␤-glucuronide. However, OATP1B3-mediated uptake of estrone-3-sulfate was stimulated 4-to 5-fold. Kinetic analysis of this stimulation revealed that the apparent affinity for estrone-3-sulfate was increased (decreased K m ), whereas the maximal rate of transport (V max ) was significantly reduced. These results demonstrate a mechanism through which the hepatic uptake of drug OATP substrates could be stimulated.

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Flavonoids as a Novel Class of Human Organic Anion-Transporting Polypeptide Oatp1b1 (Oatp-C) Modulators

Cited by 139 publications

References 37 publications

Interactions of Green Tea Catechins with Organic Anion-Transporting Polypeptides

Interactions of Green Tea Catechins with Organic Anion-Transporting Polypeptides

Hepatic Metabolism and Disposition of Baicalein via the Coupling of Conjugation Enzymes and Transporters—In Vitro and In Vivo Evidences

Isolation of Modulators of the Liver-Specific Organic Anion-Transporting Polypeptides (OATPs) 1B1 and 1B3 from Rollinia emarginata Schlecht (Annonaceae)

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