Aliases: OATP-B, OATPB, SLC21A9
Gene name: Solute carrier organic anion transporter family member 2B1 (SLCO2B1)
OATP2B1 is a ubiquitously expressed uptake transporter with broad substrate specificity. It mostly transports organic anionic endo- and xenobiotics, and its activity appears to be pH-dependent. OATP2B1 is primarily associated with the oral absorption of drugs, notably fexofenadine, whose PK is altered when intestinal OATPs and/or MDR1 are inhibited. Its expression in the liver and other tissues, as well as the results of in vitro studies, suggest a broader role in drug ADME, DDI, and toxicology; these aspects, however, are not well understood or characterized. The FDA and EMA guidances recommend evaluation of OATP drug interaction liabilities, but do not specifically recommend investigation of OATP2B1.
OATP2B1 is widely expressed in tissues including the sinusoidal membrane (blood side) of the hepatocyte, the apical membrane (gut side) of enterocytes, the basal membrane (fetal side) of the syncytiotrophoblasts, as well as the luminal membrane (blood side) of endothelial cells in brain, heart, and lung blood vessels [1-4]. OATP2B1 has been attributed tissue-specific physiological and pharmacological functions .
Function, physiology, and clinically significant polymorphisms
OATP2B1 is an organic anion uptake transporter with 12 predicted membrane-spanning domains. It exhibits pH dependency in that it seems to transport some substrates more efficiently at lower pH. Its substrate specificity appears somewhat more restricted than those of OATP1B1 and 1B3; however, it transports fexofenadine, statins, glibenclamide, glyburide, estrone 3-sulfate (E3S), dehydroepiandrosterone 3-sulfate (DHEAS), prostaglandin E2, thyroid hormones , and taurocholate.
The apparent pH dependency of transport may be important for the gastrointestinal transport of drug substrates such as fexofenadine, as pH varies substantially along the gastrointestinal tract [7, 8].
In the placenta and mammary gland, OATP2B1 plays a role in the uptake and recirculation of sulfate conjugates of steroid hormones, such as E3S and DHEAS [3, 9]. Additionally, OATP2B1 jointly with BCRP may be responsible for the transepithelial transport of E3S and DHEAS across the placenta .
OATP2B1 inhibitors include many organic anions, mono- and dicarboxylic acids [8, 10], steroid hormones and their derivatives , drugs such as rifamycin SV , pravastatin , cyclosporine, and gemfibrozil , as well as constituents of citrus juices  and herbal extracts . Of the individual components of grapefruit juice, the polymethoxiflavone nobiletin was the most potent inhibitor of OATP2B1 , and in a screen of 22 antituberculosis drugs streptomycin and linezolid had the strongest inhibitory potential on OATP2B1 .
Sequence variation in the SLCO2B1 gene has been associated with altered transport activity of the protein in vitro [7, 17], and the clinical relevance of SLCO2B1 polymorphisms is slowly emerging. SNPs like the exonic rs12422149 and the intronic rs1077858 that influence the expression levels of the protein also affect the effectiveness of androgen deprivation therapy in prostate cancer. Higher expression of OATP2B1 correlates with increased uptake of DHEAS and subsequent resistance to therapy .
FXR, HNF1α, HNF3β, and HNF4α transcriptionally regulate OATP1B1, OATP1B3, and OATP2B1 by binding to the promoter region [19-22]. Besides being substrates of OATP2B1, the thyroid hormones thyroxine (T4) and triiodothyronine (T3) are also reported to be transcriptional regulators of the transporter via transactivation of the SLCO2B1 1b and the SLCO2B1 1e promoters .
OATP2B1 in the gastrointestinal tract is involved in the oral absorption of drugs like fexofenadine (a substrate of OATP1A2, 2B1, and MDR1, amongst others) [23-26]. The oral PK of fexofenadine is altered by administration of fruit juices, which contain components that inhibit both drug transporters and drug-metabolizing enzymes. As fexofenadine is a substrate of drug transporters only, opposing roles for OATPs (facilitating absorption) and MDR1 (limiting absorption) have been proposed, although the precise contributions of these mechanisms are difficult to estimate . A recent study of the pharmacokinetics (PK) of S- and R- fexofenadine enantiomers in individuals with a range of transporter genotypes indicated a strong association of OATP2B1 polymorphism with S- enantiomer PK and OATP2B1 polymorphs in combination with other transporter polymorphs with altered R- enantiomer PK . This study not only indicates an important role for OATP2B1 in fexofenadine PK, but also illustrates the complexities of multiple transporters in multiple organs on drug PK. Grapefruit juice (at a concentration of 5%) inhibits the OATP2B1-mediated uptake of E3S by 80% . On the other hand, grapefruit juice had no effect on the pharmacokinetics of glibenclamide in healthy subjects .
OATP1B1, OATP2B1, and OATP1B3 colocalize in the same membrane domain and have overlapping substrate and inhibitor profiles. OATP2B1 in the liver mediates the hepatic uptake of many xenobiotics, including bromosulfophthalein (BSP), benzylpenicillin, fexofenadine, glibenclamide, pravastatin, atorvastatin, rosuvastatin, and fluvastatin [3, 4, 7, 8, 13, 17, 29]. Net inhibition of hepatic OATPs results in significant changes in systemic exposure and toxicities [30-32]. The relative contribution of each transporter to net hepatic uptake is unknown for almost all drugs. It is a function not only of substrate/inhibitor affinity for each transporter, but also their relative functional expression in the liver, which will vary across the population. In practice, the contribution of OATP2B1 to the hepatic uptake of drugs has not been extensively studied; most investigators cite OATP1B1 and OATP1B3 as the primary hepatic drug uptake transporters involved in DDIs.
The clinical relevance of OATP2B1 in other tissues is even less well understood. OATP2B1 is expressed on the luminal side of enterocytes, and the experimental osteoporosis drug ronacaleret interfered with OATP2B1-mediated intestinal absorption of rosuvastatin . Unlike DDIs involving hepatic OATP1Bs, this interaction decreased rather than increased rosuvastatin plasma exposure. OATP2B1 is also responsible for the intestinal uptake of the toxic irinotecan metabolite SN-38; thus, inhibition of intestinal OATP2B1 may help to prevent GI toxicity .
Overexpression of OATP2B1 has been detected in tumors of the colon, bone, breast, and prostate, as well as in gliomas. The elevated hormone uptake by OATP2B1 results in increased cell proliferation of hormone dependent tumors such as breast or prostate carcinomas. In these cases, inhibition of the transporter may be a viable strategy to inhibit tumor growth [35, 36].
The FDA and EMA guidances recommend evaluation of OATP drug interaction liabilities, but do not specifically recommend investigation of OATP2B1.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
|liver, placenta, heart, brain, kidney, lung, small intestine||bile acids, steroid hormones, thyroid hormones||coproporphyrin III, E3S, DHEAS, bromosulfophthalein, rosuvastatin||
statins, fexofenadine, glyburide, bosentan, rifampicin, aliskiren, erlotinib, balsalazide, olsalzine,
tebipenem pivoxil, unaprostone,
naringin, hesperidin, streptomycin, linezolid, ronacaleret, sulfasalazine,
tropesin, asunaprevir, ritonavir, acemetacin,
benzbromarone, tipranavir, irbesartan, ezetimibe, ketoconazole
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