Modification of OATP2B1-Mediated Transport by Steroid Hormones

Grube, Markus; Köck, Kathleen; Karner, Susanne; Reuther, Sebastian; Ritter, Christoph A.; Jedlitschky, Gabriele; Kroemer, Heyo K.

doi:10.1124/mol.106.026450

Cited by 101 publications

(89 citation statements)

References 36 publications

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“…Uptake was saturable with apparent K m and V max values of 13.8 ± 2.5 lM and 518 ± 30 pmol/mg/min, respectively. The K m value is comparable with the values published in the literature (Grube et al, 2006a;Nozawa et al, 2004;Tamai et al, 2001). …”

Section: Characterization Of Oatp2b1-expressing Cellssupporting

confidence: 81%

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

Wen

Shi

Bian

et al. 2015

Pharmaceutical Biology

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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.

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Section: Characterization Of Oatp2b1-expressing Cellssupporting

confidence: 81%

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

Wen

Shi

Bian

et al. 2015

Pharmaceutical Biology

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“…On the other hand, indomethacin, ketoprofen, and naproxen stimulated OATP2A1-mediated PGE 2 uptake in a concentration-dependent manner. Although the molecular mechanism underlying the stimulatory effect of these compounds on the OATP2A1 function is unknown, similar findings showing the stimulation of uptake transporter activities by drugs and endogenous substrates have been reported previously for transporters other than OATP2A1 (Grube et al, 2006;Bachmakov et al, 2008). Regarding OATP2A1, Lu et al (1996) also observed a slight increase of 14% in OATP2A1-mediated PGE 2 transport at a concentration of 10 M indomethacin, whereas at 100 M indomethacin the PGE 2 uptake was decreased to 82.5% of control.…”

Section: Downloaded Fromsupporting

confidence: 61%

Influence of Cyclooxygenase Inhibitors on the Function of the Prostaglandin Transporter Organic Anion-Transporting Polypeptide 2A1 Expressed in Human Gastroduodenal Mucosa

Mandery¹,

Bujok²,

Schmidt³

et al. 2009

J Pharmacol Exp Ther

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The human organic anion-transporting polypeptide 2A1 (OATP2A1) is a prostaglandin transporter expressed in several tissues and plays an important role for local distribution of prostaglandins, which contribute to the integrity of gastric mucosa. Blockade of prostaglandin pathways by cyclooxygenase (COX) inhibitors has been associated with serious side effects such as gastrointestinal ulceration and bleeding. However, little is known regarding OATP2A1 expression in the upper gastrointestinal tract and the potential impact of cyclooxygenase inhibitors on OATP2A1 function. We first investigated the expression of OATP2A1 mRNA and protein in human gastroduodenal mucosa using human biopsy specimens obtained from antrum, corpus, and duodenum. The results indicate that OATP2A1 is expressed in the neck region and deep pyloric glands of antrum and in parietal cells of gastric corpus. Second, we examined various COX inhibitors for their effects on OATP2A1 transporter activity. Using HEK293 cells expressing OATP2A1, we found that diclofenac and lumiracoxib are potent inhibitors of OATP2A1-mediated transport of prostaglandin (PG) E 2 with IC 50 values of 6.2 Ϯ 1.2 and 3.1 Ϯ 1.2 M. In contrast, indomethacin, ketoprofen, and naproxen led to significant stimulation of OATP2A1-mediated PGE 2 transport by 162.7 Ϯ 13.9, 77.2 Ϯ 3.6, and 32.3 Ϯ 4.9%, respectively. Taken together, our results suggest that various clinically used COX inhibitors have differential impact on the function of the prostaglandin transporter OATP2A1 in human stomach and that these effects may contribute to differences in the gastrointestinal side effects of COX inhibitors.

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“…Coadministration of gemfibrozil was predicted to have a minor impact on atorvastatin uptake CL, whereas coadministration of atazanavir, cyclosporine, lopinavir, and rifampicin was predicted to give a more pronounced reduction in atorvastatin uptake. previously in in vitro studies (Grube et al, 2006). To our knowledge, though, it has never been observed in vivo.…”

Section: Discussionmentioning

confidence: 81%

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

et al. 2014

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Differences in the expression and function of the organic anion transporting polypeptide (OATP) transporters contribute to interindividual variability in atorvastatin clearance. However, the importance of the bile acid transporter sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1) in atorvastatin uptake clearance (CL upt ) is not yet clarified. To elucidate this issue, we investigated the relative contribution of NTCP, OATP1B1, OATP1B3, and OATP2B1 to atorvastatin CL upt in 12 human liver samples. The impact of inhibition on atorvastatin CL upt was also studied, using inhibitors of different isoform specificities. Expression levels of the four transport proteins were quantified by liquid chromatography tandem mass spectrometry. These data, together with atorvastatin in vitro kinetics, were used to predict the maximal transport activity (MTA) and interindividual differences in CL upt of each transporter in vivo. Subsequently, hepatic uptake impairment on coadministration of five clinically interacting drugs was predicted using in vitro inhibitory potencies. NTCP and OATP protein expression varied 3.7-to 32-fold among the 12 sample donors. The rank order in expression was OATP1B1 > OATP1B3 NTCP OATP2B1. NTCP was found to be of minor importance in atorvastatin disposition. Instead, OATP1B1 and OATP1B3 were confirmed as the major atorvastatin uptake transporters. The average contribution to atorvastatin uptake was OATP1B1 > OATP1B3 >> OATP2B1 > NTCP, although this rank order varied among individuals. The interindividual differences in transporter expression and CL upt resulted in marked differences in drug-drug interactions due to isoform-specific inhibition. We conclude that this variation should be considered in in vitro to in vivo extrapolations.

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Modification of OATP2B1-Mediated Transport by Steroid Hormones

Cited by 101 publications

References 36 publications

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

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

Influence of Cyclooxygenase Inhibitors on the Function of the Prostaglandin Transporter Organic Anion-Transporting Polypeptide 2A1 Expressed in Human Gastroduodenal Mucosa

Hepatic Uptake of Atorvastatin: Influence of Variability in Transporter Expression on Uptake Clearance and Drug-Drug Interactions

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