OATP1B1 Transporter Assay (SLCO1B1)

The Organic Anion Transporting Polypeptide 1B1, or OATP1B1, is expressed on the sinusoidal (basolateral) membrane of human hepatocytes, and is one of the most highly expressed transporters in the human liver.  It has broad substrate specificity and can transport numerous anions, zwitterions, and neutral molecules.  Endogenous substrates include bile acids, steroid hormone conjugates, thyroid hormones, bilirubin, and various sulfate and glucuronide conjugates.  OATP1B1 is also responsible for the hepatic uptake of many therapeutic reagents, most notably members of the statin family, as well as bosentan, repaglinide, and others.  OATP1B1 can also be inhibited by many commonly used medications, including macrolide antibiotics (such as erythromycin), protease inhibitors (such as ritonavir), gemfibrozil, rifampicin, and cyclosporine.  As a result, numerous clinically relevant drug-drug interactions are known to be mediated by OATP1B1.

Three members of the OATP family — OATP1B1, OATP1B3, and OATP2B1 – are all expressed together in human hepatocytes. There is considerable overlap in the substrate specificities of these three transporters, although some compounds do demonstrate selectivity.  Pitavastatin and prostaglandin E2 have been reported to be transported only by OATP1B1, while cholecystokinin octapeptide (CCK-8) and paclitaxel are specific for OATP1B3.

In preclinical species, there may be significant differences in OATP-mediated hepatic uptake from that seen in humans, complicating direct comparisons.  Rodents do not express OATP1B1 or OATP1B3, but rather a single ortholog in liver, Oatp1b2.  The predominant Oatp family member in canine liver is Oatp1b4, which recognizes a similar but not identical range of substrates as human OATP1B1 and OATP1B3.  These differences in transporters may contribute to species differences in the hepatic uptake and elimination of drugs.

OATP1B1 also has relatively common polymorphisms that can alter the pharmacokinetics of several therapeutic agents.  The T521C (Val174Ala) and A388G (Asn130Asp) variants have been shown to increase the AUC and Cmax of several statins.  The T521C variant has also been reported to result in an attenuated response to statin therapy, as well as being associated with the toxic side effects of irinotecan and methotrexate chemotherapy.  OATP1B1 variants are also strongly associated with an increased risk of simvastatin-induced myopathy.

Both the FDA and EMA recommend that all investigational drugs be tested as potential inhibitors of OATP1B1, and that they also be tested as potential substrates of OATP1B1 if liver is responsible for elimination.

Optivia’s OATP1B1 Assay

Optivia offers OATP1B1 substrate and inhibition assays in polarized mammalian cells.  We offer a wide range of studies, from single concentration screens up to full kinetic studies that allow the determination of IC50 values for inhibitors, as well as Km and Vmax values for substrates.

In addition, we offer OATP1B1 in multiple-transporter formats in which uptake transporters (such as OATP1B1) are expressed along with efflux transporters (such as BCRP, MRP2, or BSEP) to investigate biologically relevant vectorial transport.

OATP1B1 Transporter Assay Details

Relevance – FDA & EMA guidance, hepatic uptake, drug-drug interactions Single or Multi-Transporter Model – Single (Multi-Transporter models are also available)
Transporter Type – Uptake Cell Model – MDCK-II
Assay Type – Intracellular accumulation (Transcellular assay for Multi-Transporter models) Exactly Matched Control Cells – Yes
Species – Human Probe Substrate – Estradiol-17-ß-D-glucuronide
Subcellular Localization in Assay Model – Basolateral Inhibition Positive Control – Rifampicin

Clinical & Regulatory Relevance

OATP1B1 is important for the uptake of many pharmaceuticals into the liver.  Compounds that are substrates of OATP1B1 may have their pharmacokinetic properties altered by other substrates or inhibitors of OATP1B1 and become “victims” of a drug-drug interaction.  Compounds that are inhibitors of OATP1B1 may become “perpetrators” of drug-drug interactions with co-medications, altering the pharmacokinetic properties of the co-medication.  Both the FDA and EMA recommend that investigational new drugs be tested as potential inhibitors of OATP1B1.  If the clearance of the investigational new drug is mediated by the liver, the FDA and EMA also recommend that it be tested as a potential substrate of OATP1B1.

Applications & Therapeutic AreasOATP1B1-transporter-Liver

DDI/regulatory, hepatic uptake, potential use in cancer chemotherapy.

Related Resources

The roles of MRP2, MRP3, OATP1B1, and OATP1B3 in conjugated hyperbilirubinemia.

Organic anion-transporting polypeptides: a novel approach for cancer therapy.

New insights in bilirubin metabolism and their clinical implications.

Transporter biology in drug approval: regulatory aspects.

Classification of inhibitors of hepatic organic anion transporting polypeptides (OATPs): influence of protein expression on drug-drug interactions.

Transporter-mediated drug-drug interactions.

Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions.

Organic anion transporting polypeptide 1B1: a genetically polymorphic transporter of major importance for hepatic drug uptake.

SLCO1B1 variants and statin-induced myopathy–a genomewide study.