Human Transporters


OATP1A2 (organic anion transporting polypeptide 1A2)

Aliases: OATP, OATP-A, SLC21A3
Gene name: Solute carrier organic anion transporter family member 1A2 (SLCO1A2)


OATP1A2, the first identified human OATP, is an uptake transporter with widespread tissue expression. It has broad substrate specificity, including endogenous amphipathic substrates as well as pharmacological drugs and xenobiotics. It is expressed in all major organs, particularly on the apical surface of enterocytes and cholangiocytes (in contrast to OATP1B1 and 1B3, which are both expressed on the basolateral surface of hepatocytes), as well as in the brain, lung, kidney, and testis [1-3]. Its expression in the liver and gastrointestinal tract (GIT) is altered in the presence of excess bile acids (although the data are somewhat ambiguous), and expression can also be influenced by steroid receptors and the vitamin D receptor. The clinical relevance of this remains unclear. Given the promiscuity of this transporter, and its expression in organs of relevance to drug disposition and response, genetic variations in SLCO1A2 have the potential for significant pharmacologic and toxicological consequences. Once again, the clinical relevance of these observations remains to be clearly demonstrated. However, OATP1A2 is notably inhibited in the human GIT by components of fruit juice, which decrease the oral bioavailability of the OATP1A2 (and MDR1) substrate fexofenadine [4-6]. Although the evidence indicates that OATP1A2-mediated oral absorption of some drugs is modified by foods, and that this transporter has broad substrate specificity for important therapeutic drug classes, neither the FDA nor the EMA guidance specifically recommend the study of OATP1A2 interactions for NCEs.


OATP1A2 mRNA is expressed in all major organs of the human body [1-3, 7]. In the intestine, OATP1A2 protein is localized to the brush border (apical) membrane of enterocytes in the duodenum, where it is implicated in the oral absorption of xenobiotics [6]. Within the liver, OATP1A2 is exclusively expressed on the apical (biliary) membrane of cholangiocytes, and may be involved in the reabsorption of substrates that have been excreted into the bile [8]. In the kidney, OATP1A2 is expressed at the apical (urine) membrane of the distal nephron, where it may be responsible for either reabsorption or secretion of xenobiotics into urine [8]. OATP1A2 is also expressed apically in capillary endothelial cells of the blood–brain barrier (BBB) [9] and in retinal pigment epithelial cells [10], and it is found in the red blood cell membrane [11].
OATP1A2 expression in normal nonmalignant breast tissue is low as compared with other members of the OATP family. However, expression in lactating mammary epithelium cells (MEC) is significantly greater than non-lactating MECs, suggesting a regulated physiological function of this transporter in breast tissue [12, 13].
Function, physiology, and clinically significant polymorphisms
OATP1A2 is an integral membrane protein, predicted to contain 12 membrane-spanning domains. It is generally regarded as a unidirectional uptake transporter. In common with many other OATPs, the driving forces facilitating its transport activity remain somewhat unclear. OATP1A2 transports a diverse range of organic anionic, neutral, cationic and amphipathic xenobiotic and endogenous molecules, including bile acids, conjugated sex steroids, T3 and T4, linear and cyclic peptides, mycotoxins, prostaglandin E2, fexofenadine, ouabain, and statins [2, 7, 14-16]. Several drugs, such as saquinavir, lovastatin, verapamil, dexamethasone and naloxone, and food components such as fruit juices and naringin, inhibit OATP1A2-mediated substrate uptake in vitro [17].
High expression of OATP1A2 in the BBB, kidney, and liver, and its affinity for T3 and T4, indicate a potentially important role in the delivery of thyroid hormones to the kidney and across the BBB, as well as elimination by the liver [18]. OATP1A2 is essential to all-trans-retinol uptake by retinal pigment epithelial cells, which is part of the canonical visual cycle [10].
Cholestasis has been associated with decreased mRNA levels of hepatic OATP1A2, OATP1B1, and OATP1B3 [19, 20]. However, other studies report up-regulation of OATP1A2 expression in the small intestine and liver in response to increased bile acid levels [3]. Similarly, placental expression of OATP1A2 mRNA is increased in patients with intrahepatic cholestasis during pregnancy [21]. Albeit contradictory, these studies indicate a direct or indirect role for OATP1A2 in bile salt transport.
Altered expression levels and single nucleotide polymorphisms (SNPs) of OATP1A2 are associated with disease states and altered drug disposition. Lee et al. identified and functionally characterized SLCO1A2 SNPs in a population of mixed European, Chinese, Hispanic and African-American descent [8], and the clinical relevance of SLCO1A2 polymorphisms was more recently reviewed by Zhou et al. [22]. Genotypic frequencies of six non-synonymous polymorphisms within the coding region of SLCO1A2 were dependent on ethnicity, and some of the genetic variants were associated with markedly reduced in vitro uptake transport activity [8]. In vitro studies examining the impact of OATP1A2 polymorphisms and altered pH on the uptake of methotrexate (a substrate of multiple transporters) indicated that OATP1A2 may be important in the toxicity and elimination of this drug [23]. OATP1A2 contributed significantly to doxorubicin uptake in vitro, and polymorphic variants were associated with significantly impaired doxorubicin transport in vitro as well as altered disposition in vivo [24, 25]. OATP1A2 polymorphisms are associated with differences in the pharmacokinetics of imatinib clearance [26]. Thus, SLCO1A2 polymorphisms may contribute to inter-individual variability in drug disposition and clearance.
Expression of OATPs is largely controlled by transcriptional regulation. In breast carcinoma tissues and cell lines, OATP1A2 expression is significantly associated with the expression of the steroid and xenobiotic receptor (SXR) [27]. Regulation of OATPs can also occur at the protein level. As most OATPs contain a PDZ consensus sequence [28], and the carboxyl terminus of OATP1A2 has been shown to interact with PDZ proteins, membrane localization of OATPs may be due to interactions with PDZ proteins [29]. Protein kinase C (PKC) regulates the transport function of OATP1A2 by modulating protein internalization; this effect of PKC is mediated in part by clathrin-dependent pathways in an in vitro cell model [30]. Targeting, internalization, and recycling of OATP1A2 is also dependent on casein kinase 2 [31].
A role for PXR in OATP1A2 regulation has been suggested and related to the pathophysiology of breast cancer; therefore, these proteins may be novel therapeutic targets for intervention [32]. Treatment of Caco-2 cells with vitamin D3 markedly increased endogenous OATP1A2 mRNA and protein levels through interaction with the vitamin D receptor (VDR), suggesting that oral dosing of vitamin D3 may modulate intestinal absorption of OATP1A2 substrates [33], although this has not been demonstrated clinically thus far.

Clinical significance

The majority of drug interactions on OATP1A2 are ascribed to inhibition of transport in the GIT. Although many OATP-mediated DDIs have been reported [34] and [35], these are primarily associated with the basolaterally expressed hepatic transporters OATP1B1 and 1B3, whereas OATP1A2 (and OATP2B1) are expressed at the luminal membrane of enterocytes.
Reported OATP1A2 interactions typically involve dietary components rather than drugs, although tricyclic antidepressants with a short aliphatic amine chain were found to inhibit OATP1A2-mediated rosuvastatin transport [36]. Fruit juices decrease the oral bioavailability of fexofenadine in humans at least in part by inhibition of OATP1A2 [4-6]. Uptake of fexofenadine is inhibited by naringin, a component of grapefruit and orange juice (at 5% soft drink strength) in vitro. In healthy subjects, the AUC of fexofenadine was decreased 25% by ingestion of naringin, and by 40–70% after ingestion of grapefruit or orange juice, consistent with inhibition of OATP1A2 at the apical membrane of enterocytes [4-6, 37]. In another in vivo study with 10 healthy participants, catechins in green tea interfered with the absorption of the beta-blocker nadolol and decreased nadolol plasma exposure by 85% partly through inhibition of OATP1A2 [38].
Many flavonoids affect OATP-mediated uptake of the model substrates estrone-3-sulphate, estradiol- 17-glucuronide and dehydroepiandrosterone-3-sulphate (DHEAS), suggesting that possible drug–food interactions could occur especially in patients taking over-the-counter dietary supplements in addition to prescribed medications [39, 40]. Other potential drug-food interactions continue to emerge from in vitro investigations (e.g. the Ginkgo flavonoids, apigenin, kaempferol, and quercetin inhibit OATP1A2 and OATP2B1 transport activity [41], and OATP1A2 transport of the fluoroquinolone antibiotic levofloxacin is inhibited by other quinolones [42]).

Regulatory Requirements

Although the evidence indicates that OATP1A2-mediated oral absorption of some drugs is modified by foods, and that this transporter has broad substrate specificity for important therapeutic drug classes, neither the FDA nor the EMA guidance specifically recommends the study of OATP1A2 interactions for NCEs.

Location Endogenous substrates In vitro substrates used experimentally Substrate drugs Inhibitors
brain, kidney, liver, intestine cholic acid, DHEAS
prostaglandin E2
T3, T4,
conjugated sex steroids,
linear and cyclic peptides

erythromycin, fexofenadine, imatinib, levofloxacin and other fluoroquinolones, lopinavir, methotrexate,
rocuronium ,
Statins (rosuvastatin,
ouabain, saquinavir,
deltophorin II, DPDPE,
unaprostone, acebutolol,
atenolol, atrasentan ,
celiprolol, sotalol, talinolol, tebipenem , pivoxil

fruit juices (apple, grapefruit, orange, pomelo)
hesperidins, naringin, rifampicin, rifamycin, verapamil



1.    Steckelbroeck, S., et al., Steroid sulfatase (STS) expression in the human temporal lobe: enzyme activity, mRNA expression and immunohistochemistry study. J Neurochem, 2004. 89(2): p. 403-17.
2.    Kullak-Ublick, G.A., et al., Molecular and functional characterization of an organic anion transporting polypeptide cloned from human liver. Gastroenterology, 1995. 109(4): p. 1274-82.
3.    Kullak-Ublick, G.A., et al., Identification and functional characterization of the promoter region of the human organic anion transporting polypeptide gene. Hepatology, 1997. 26(4): p. 991-7.
4.    Dresser, G.K., et al., Fruit juices inhibit organic anion transporting polypeptide-mediated drug uptake to decrease the oral availability of fexofenadine. Clin Pharmacol Ther, 2002. 71(1): p. 11-20.
5.    Dresser, G.K., R.B. Kim, and D.G. Bailey, Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides. Clin Pharmacol Ther, 2005. 77(3): p. 170-7.
6.    Glaeser, H., et al., Intestinal drug transporter expression and the impact of grapefruit juice in humans. Clin Pharmacol Ther, 2007. 81(3): p. 362-70.
7.    Roth, M., A. Obaidat, and B. Hagenbuch, OATPs, OATs and OCTs: the organic anion and cation transporters of the SLCO and SLC22A gene superfamilies. Br J Pharmacol, 2012. 165(5): p. 1260-87.
8.    Lee, W., et al., Polymorphisms in human organic anion-transporting polypeptide 1A2 (OATP1A2): implications for altered drug disposition and central nervous system drug entry. J Biol Chem, 2005. 280(10): p. 9610-7.
9.    Bronger, H., et al., ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res, 2005. 65(24): p. 11419-28.
10.    Chan, T., et al., Human organic anion transporting polypeptide 1A2 (OATP1A2) mediates cellular uptake of all-trans-retinol in human retinal pigmented epithelial cells. Br J Pharmacol, 2015. 172(9): p. 2343-53.
11.    Hubeny, A., et al., Expression of Organic Anion Transporting Polypeptide 1A2 in Red Blood Cells and Its Potential Impact on Antimalarial Therapy. Drug Metab Dispos, 2016. 44(10): p. 1562-8.
12.    Pizzagalli, F., et al., Identification of steroid sulfate transport processes in the human mammary gland. J Clin Endocrinol Metab, 2003. 88(8): p. 3902-12.
13.    Alcorn, J., et al., Transporter gene expression in lactating and nonlactating human mammary epithelial cells using real-time reverse transcription-polymerase chain reaction. J Pharmacol Exp Ther, 2002. 303(2): p. 487-96.
14.    Cvetkovic, M., et al., OATP and P-glycoprotein transporters mediate the cellular uptake and excretion of fexofenadine. Drug Metab Dispos, 1999. 27(8): p. 866-71.
15.    Gao, B., et al., Organic anion-transporting polypeptides mediate transport of opioid peptides across blood-brain barrier. J Pharmacol Exp Ther, 2000. 294(1): p. 73-9.
16.    Hagenbuch, B. and P.J. Meier, Organic anion transporting polypeptides of the OATP/ SLC21 family: phylogenetic classification as OATP/ SLCO superfamily, new nomenclature and molecular/functional properties. Pflugers Arch, 2004. 447(5): p. 653-65.
17.    Kullak-Ublick, G.A., et al., Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain. FEBS Lett, 1998. 424(3): p. 173-6.
18.    Ianculescu, A.G., et al., Transport of thyroid hormones is selectively inhibited by 3-iodothyronamine. Mol Biosyst, 2010. 6(8): p. 1403-10.
19.    Keitel, V., et al., Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Hepatology, 2005. 41(5): p. 1160-72.
20.    Congiu, M., et al., Coordinate regulation of metabolic enzymes and transporters by nuclear transcription factors in human liver disease. J Gastroenterol Hepatol, 2009. 24(6): p. 1038-44.
21.    Cui, T., et al., Bile acid transport correlative protein mRNA expression profile in human placenta with intrahepatic cholestasis of pregnancy. Saudi Med J, 2009. 30(11): p. 1406-10.
22.    Zhou, Y., et al., Genetic polymorphisms and function of the organic anion-transporting polypeptide 1A2 and its clinical relevance in drug disposition. Pharmacology, 2015. 95(3-4): p. 201-8.
23.    Badagnani, I., et al., Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants. J Pharmacol Exp Ther, 2006. 318(2): p. 521-9.
24.    Durmus, S., et al., In vivo disposition of doxorubicin is affected by mouse Oatp1a/1b and human OATP1A/1B transporters. Int J Cancer, 2014. 135(7): p. 1700-10.
25.    Lee, H.H., et al., Contribution of Organic Anion-Transporting Polypeptides 1A/1B to Doxorubicin Uptake and Clearance. Mol Pharmacol, 2017. 91(1): p. 14-24.
26.    Yamakawa, Y., et al., Pharmacokinetic impact of SLCO1A2 polymorphisms on imatinib disposition in patients with chronic myeloid leukemia. Clin Pharmacol Ther, 2011. 90(1): p. 157-63.
27.    Miki, Y., et al., Expression of the steroid and xenobiotic receptor and its possible target gene, organic anion transporting polypeptide-A, in human breast carcinoma. Cancer Res, 2006. 66(1): p. 535-42.
28.    Wang, P., et al., Interaction with PDZK1 is required for expression of organic anion transporting protein 1A1 on the hepatocyte surface. J Biol Chem, 2005. 280(34): p. 30143-9.
29.    Kato, Y., et al., Screening of the interaction between xenobiotic transporters and PDZ proteins. Pharm Res, 2004. 21(10): p. 1886-94.
30.    Zhou, F., et al., Protein kinase C regulates the internalization and function of the human organic anion transporting polypeptide 1A2. Br J Pharmacol, 2011. 162(6): p. 1380-8.
31.    Chan, T., et al., Casein Kinase 2 Is a Novel Regulator of the Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2) Trafficking. Mol Pharm, 2016. 13(1): p. 144-54.
32.    Meyer zu Schwabedissen, H.E., et al., Interplay between the nuclear receptor pregnane X receptor and the uptake transporter organic anion transporter polypeptide 1A2 selectively enhances estrogen effects in breast cancer. Cancer Res, 2008. 68(22): p. 9338-47.
33.    Eloranta, J.J., et al., The SLCO1A2 Gene, Encoding the Human Organic Anion Transporting Polypeptide 1A2 (OATP1A2), is Transactivated by the Vitamin D Receptor (VDR). Mol Pharmacol, 2012.
34.    Neuvonen, P.J., M. Niemi, and J.T. Backman, Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther, 2006. 80(6): p. 565-81.
35.    Treiber, A., et al., Bosentan is a substrate of human OATP1B1 and OATP1B3: inhibition of hepatic uptake as the common mechanism of its interactions with cyclosporin A, rifampicin, and sildenafil. Drug Metab Dispos, 2007. 35(8): p. 1400-7.
36.    Lu, J., et al., Effects of beta-blockers and tricyclic antidepressants on the activity of human organic anion transporting polypeptide 1A2 (OATP1A2). J Pharmacol Exp Ther, 2015. 352(3): p. 552-8.
37.    Bailey, D.G., et al., Naringin is a major and selective clinical inhibitor of organic anion-transporting polypeptide 1A2 (OATP1A2) in grapefruit juice. Clin Pharmacol Ther, 2007. 81(4): p. 495-502.
38.    Misaka, S., et al., Green tea ingestion greatly reduces plasma concentrations of nadolol in healthy subjects. Clin Pharmacol Ther, 2014. 95(4): p. 432-8.
39.    Wang, X., A.W. Wolkoff, and M.E. Morris, Flavonoids as a novel class of human organic anion-transporting polypeptide OATP1B1 (OATP-C) modulators. Drug Metab Dispos, 2005. 33(11): p. 1666-72.
40.    Roth, M., B.N. Timmermann, and B. Hagenbuch, Interactions of green tea catechins with organic anion-transporting polypeptides. Drug Metab Dispos, 2011. 39(5): p. 920-6.
41.    Mandery, K., et al., Influence of the flavonoids apigenin, kaempferol, and quercetin on the function of organic anion transporting polypeptides 1A2 and 2B1. Biochem Pharmacol, 2010. 80(11): p. 1746-53.
42.    Maeda, T., et al., Identification of influx transporter for the quinolone antibacterial agent levofloxacin. Mol Pharm, 2007. 4(1): p. 85-94.


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