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Understanding the role of OATP2B1 in drug delivery and disposition

Much of the research into SLC transporters has focused on related family members, OATP1B1 and OATP1B3. However, our knowledge of OATP2B1 is increasing as we learn more about its importance in delivery and disposition of drugs and endogenous substances. OATP2B1 is expressed in the apical membrane of the small intestine and the blood brain barrier and the hepatocyte basolateral membrane. However, its expression is fairly ubiquitous and it is also found in lung, muscle and platelets where it controls intracellular drug accumulation. OATP2B1 mediates the cellular uptake of a range of amphipathic organic compounds, including bile salts, steroid conjugates, thyroid hormone and numerous drugs. Its transport activity is highly pH dependent. Activity increases at lower pH values, and it has broader substrate specificity at an acidic pH (pH 6.8) for various endogenous molecules and drugs. At pH 7.4, OATP2B1 transports mainly steroid hormone conjugates.

OATP2B1 is known to be expressed in a number of solid tumours. This has proved an interesting target for novel cancer therapies where active uptake into tumours is being considered. Indeed, the solid tumour environment tends to be acidic and so increases the activity of OATP2B1. The acidic environment in the small intestine is also thought to increase the uptake activity of OATP2B1 in the intestinal tract, and there may be the opportunity to utilise the transporter as a tool in drug delivery.

Whilst the FDA and EMA do not currently recommend that OATP2B1 is evaluated as a standard transporter within regulatory drug-drug interaction (DDI) studies, it has been recognised by the International Transporter Consortium (ITC) as a transporter of emerging clinical interest.

Understanding if a substance is a substrate or inhibitor of OATP2B1 is now possible as cell lines which express this transporter are available. Typical studies involve understanding if pharmaceuticals are substrates for this transporter as a mechanism for drug delivery, identifying mechanisms of organ or tissue-based toxicity, or determining DDI potential for certain chemical classes.

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