OATP1B3 (SLCO1B3) Transporter Assay
Organic anion transporting polypeptide 1B3 (OATP1B3) is an uptake transporter encoded by the SLCO1B3 gene. The protein is expressed on the sinusoidal (basolateral) membrane of human hepatocytes, and has broad substrate specificity. Endogenous substrates include bile acids, steroid hormone conjugates, thyroid hormones, bilirubin, and various sulfate and glucuronide conjugates. OATP1B3 is also responsible for the hepatic uptake of many therapeutic agents, including members of the statin family, as well as bosentan, methotrexate, paclitaxel, telmisartan, and others. OATP1B3 can be inhibited by many commonly used medications, including protease inhibitors (such as ritonavir), repaglinide, rifampicin, and cyclosporine. As a result, numerous clinically relevant drug-drug interactions are known to be mediated by OATP1B3.
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.
While polymorphisms have been identified for OATP1B3, the evidence for the clinical importance of these variants is less clear than it is for OATP1B1. OATP1B3 has been reported to be overexpressed in colorectal and breast cancers, which could make it an attractive target for delivery of chemotherapeutics.
Both the FDA and EMA recommend that all investigational drugs be tested as potential inhibitors of OATP1B3, and that they also be tested as potential substrates of OATP1B3 if the liver is responsible for elimination.
Clinical & Regulatory Relevance
OATP1B3 is important for the uptake of many pharmaceuticals into the liver. Compounds that are substrates of OATP1B3 may have their pharmacokinetic properties altered by other substrates or inhibitors of OATP1B3 and become “victims” of a drug-drug interaction. Compounds that are inhibitors of OATP1B3 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 OATP1B3. 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 OATP1B3.
Applications & Therapeutic Areas
DDI/regulatory, hepatic uptake, potential use in cancer chemotherapy.
BioIVT’s OATP1B1 Assay
BioIVT offers OATP1B3 substrate and inhibition assays in polarized mammalian cells. We offer a wide range of studies, from single concentration screens 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 OATP1B3 in multiple-transporter formats in which uptake transporters (such as OATP1B3) are expressed along with efflux transporters (such as BCRP, MRP2, or BSEP) to investigate biologically-relevant vectorial transport.
OATP1B3 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 – CCK-8
|Subcellular Localization in Assay Model – Basolateral
||Inhibition Positive Control – Rifampicin