ABCG2/BCRP: variants, transporter interaction profile of substrates and inhibitors

ABSTRACT

Introduction: ABCG2 has a broad substrate specificity and is one of the most important efflux proteins modulating pharmacokinetics of drugs, nutrients and toxicokinetics of toxicants. ABCG2 is an important player in transporter-mediated drug–drug interactions (tDDI).

Areas covered: The aims of the review are i) to cover transporter interaction profile of substrates and inhibitors that can be utilized to test interaction of drug candidates with ABCG2, ii) to highlight main characteristics of in vitro testing and iii) to describe the structural basis of the broad substrate specificity of the protein. Preclinical data utilizing Abcg2/Bcrp1 knockouts and clinical studies showing effect of ABCG2 c.421C>A polymorphism on pharmacokinetics of drugs have provided evidence for a broad array of drug substrates and support drug – ABCG2 interaction testing. A consensus on using rosuvastatin and sulfasalazine as intestinal substrates for clinical studies is in the formation. Other substrates relevant to the therapeutic area can be considered. Monolayer efflux assays and vesicular transport assays have been extensively utilized in vitro.

Expert opinion: Clinical substrates display complex pharmacokinetics due to broad interaction profiles with multiple transporters and metabolic enzymes. Substrate-dependent inhibition has been observed for several inhibitors. Harmonization of in vitro and in vivo testing makes sense. However, rosuvastatin and sulfasalazine are not efficiently transported in either MDCKII or LLC-PK1-based monolayers. Caco-2 monolayer assays and vesicular transport assays are potential alternatives.

KEYWORDS:

• ABCG2
• in vitro
• BCRP
• clinical
• inhibitors
• probe substrates

Highlights

• ABCG2 is a broad substrate specificity transporter with multiple drug-binding regions.

• Of in vitro test systems monolayers and vesicular transport assays are the most applicable for low permeability drugs. Caco-2 systems and vesicles work with rosuvastatin and sulfasalazine.

• Several substrates have displayed an ABCG2 specific/selective transport in vitro-, with phytoestrogens and estrone-3-sulfate displaying the most specific profile.

• Among ABCG2-specific/selective inhibitors the Fumitremorgin C (FTC) family and lapatinib has been shown to work well in monolayers.

• In addition to rosuvastatin and sulfasalazine, novel drugs including several HIV integrase inhibitors and direct oral anticoagulants have displayed ABCG2-dependent pharmacokinetics.

• The broad substrate specificity inhibitor Cyclosporine A, in addition to more selective ABCG2 inhibitors curcumin, eltrombopag, and lapatinib can be used in the clinic.

• Additional recently characterized drugs can be used as ABCG2 inhibitors.

Declaration of interest

P Krajcsi, Z Safar, E Kis, and JK Zolnerciks are employees of Solvo Biotechnology, a company that specializes in development and commercialization of transporter technology applications. P Krajcsi, Z Safar, and E Kis report grant: GINOP-2.2.1-15-2016-00009. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the NRDI under Grant: GINOP-2.2.1-15-2016-00009.