Organic Anion Transporter Polypedtides

OATP1B1 (SLCO1B1), OATP1B3 (SLCO1B3), OATP1A2 (SLCO1A2) and OATP2B1 (SLCO2B1) Transporters

OATP: What and Where

The organic anion transporter polypedtides (OATPs; SLCO) represent a superfamily of transporters. Regardless of their name, these ubiquitously expressed transporter proteins have a broad range substrate profile, from endogenous compounds, such as bile salts and hormones, to peptide and other xenobiotic products.1 Of this large superfamily, OATP1B1 (aka OATP-C, OATP2, LST-1; gene: SLCO1B1) and OATP1B3 (aka OATP-8; gene: SLCO1B3) have come to the forefront, most commonly indicted in drug-drug interactions. To a lesser extent, OATP1A2 (aka OATP-A; gene: SLCO1A2) and OATP2B1 (aka OATP-B; gene: SLCO2B1), which are both expressed at the blood-brain barrier, liver, and intestines have also been shown to play a role in drug pharmacokinetics.


Blood Brain Barrier

MATE+Transporter+Liver drug transporters BBB uptake

Intestinal Epithelia

Drug Transporter Intestinal Uptake

 OATP Clinical Importance

Being expressed on many, if not all, of the major absorptive membrane surfaces throughout the body, it is not surprising that OATPs play a major role in the influx of endogenous compounds as well as clinically important drugs.2 Thus, their impact in the absorption, distribution and excretion of pharmacologically active drugs throughout the body can lead to increased drug-drug interaction risk. It is worth noting, genetic variants due to SNPs can have a dramatic effect on the drug:transporter interaction, particularly in the case of OATP1B1.2 Additionally, OATPs expressed in the liver appear to work in concert with P450 metabolizing enzymes, as it has been shown that there is large substrate overlap, as well as several noteworthy, complex DDIs have be identified.2

OATP Regulatory Significance

Due to their broad specificity, the number of known DDIs, as well as their interaction with statins1, hepatic uptake transporters OATP1B1 and OATP1B3 have been deemed clinically relevant by the agencies. In both the European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions(effective: January 2013) and the US Food and Drug Administration (FDA) Guidance for the Industry: Drug Interactions Studies (issued: Feb 2012), OATP1B1 and OATP1B3 are named specifically as clinically relevant transporters, and it is “recommended” to investigate OATP1B1 and OATP1B3 inhibitor potential of all new drugs. With regard to assessment of substrate potential, once again, the Agencies agree. OATP1B1 and OATP1B3 substrate potential should be assessed clearance of the compounds, specifically if “≥ 25% of elimination is hepatic”.3

OATP1A2 and OATP2B1 have not been explicitly named by either agency, yet; however, according to the EMA:

“The knowledge about transporters and their in vivo importance is evolving quickly. The choice of transporters investigated should be driven by scientific evidence, and transporters may be added to or removed from the list as science develops. In addition to the listed transporters, there may also be a need to investigate effects on other transporters to clarify the mechanism of an unexpected interaction observed in vivo.” 3

Thus, though they are currently deemed as part of the top 9 to 11 transporter named by the FDA and EMA, respectively, transporter science continues to evolve and the agencies may ask for additional information based on unexpected in vivo data.

Clinically Relevant Probe Substrates and Inhibitors

Substrates Inhibitors
atrasentan, atrovastatin*, bosentan, ezetimibe, fluvastatin, glyburide, SN-38, rosuvastatin*, simvastatin acid, pitavastatin, pravastatin, repaglinide, rifampin, valsartian, olmesartan atazanavir, cyclosporine, eltrombopag, gemfibrozil, lopinavir, rifamycin SV‡, ritonavir‡, saquinavir, tipranavir
Substrates Inhibitors
atorvastatin*, rosuvastatin*, pitavastatin, telmisartan, valsartan, olmesartan atazanavir, cyclosporine, lopinavir, rifamycin SV‡, ritonavir‡, saquinavir, tipranavir
Substrates Inhibitors
fexofenadine, digoxin, levofloxacin, atorvastatin* ritonavir‡, lopinavir, saquinavir, rifampicin
Substrates Inhibitors
taurocholate, fexofenadine, rosuvastatin* rifamycin SV‡, cyclosporine
*Probe substrate validated by Absorption Systems
‡Inhibitor validated by Absorption Systems

OATP In Vitro Model

We have stably transfected HEK293 cells separately with hOATP1B1, hOATP1B3, hOATP1A2, and hOATP2B1, and have validated a stable, clonally-selected, robust cell-based assay in which transporter function.

1. Giacomini KM, et al. (2010) Membrane transporters in drug development. Nature Reviews Drug Disc. 9(3):215-236
2. Kalliokoski A and M Neimi. (2009) Impact of OATP transporters on pharmacokinetics. Br J Pharmacology 158: 693-7053.
3. European Medicines Agency (Jun 2012) Guideline on the Investigation of Drug Interactions
4. US Food and Drug Administration (Feb 2012) Draft Guidance for Industry: Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing and Labeling Recommendations