Choosing Appropriate Model to Assess PROTAC Drug-Drug Interactions with Efflux Transporters

Drug transporters can be major determinants of drug pharmacokinetics. To evaluate the drug interactions with these drug transporters, suitable in vitro methods or models should be applied. The literature has revealed that the drug interactions between a PROTAC* (Proteolysis-Targeting Chimera) drug and rosuvastatin are mediated by the inhibition of breast cancer resistance protein (BCRP) transporter.¹ BCRP is a major ATP-binding cassette (ABC) transporter protein that plays a vital role in drug transport and rosuvastatin is a known BCRP substrate. Based on our research experience, evaluating in vitro transporter studies of PROTAC molecules presents some challenges. Improper model selection may lead to erroneous results and mislead the assessment of Drug–Drug interactions (DDI) risk.

What is an appropriate study model for the inhibition of BCRP by PROTAC?

It is vital to choose an appropriate transporter model to assess the risk of DDI of PROTAC. In vitro transporter inhibition assays can be evaluated using Caco-2 cells, cells with a high expression of BCRP, or membrane vesicles with a high expression of BCRP. We first assessed the inhibitory effect of a PROTAC molecule on BCRP using a Caco-2 cell model, which showed no inhibition and was inconsistent with the literature.

Based on this problem, we switched to a membrane vesicle model. Membrane vesicles expose the substrate binding sites of ABC transporters to extracellular buffers and thus the inhibitor can be in direct contact with the transporter substrate binding site outside the membrane. The vesicle method showed that the PROTAC molecule had a strong inhibitory effect on BCRP, which was consistent with the previous literature reports.

In conclusion, the membrane vesicle model may be more suitable to study the inhibitory effect of low-permeability PROTAC molecules on the efflux transporter. In addition to BCRP, the same problem may exist in the inhibition of other efflux transporters by PROTAC molecules. It is necessary to pay attention to the model selection in studying the inhibition of efflux transporters by PROTAC molecules.

If you want to learn more details about the DDI between PROTAC and efflux transporters, please read the article now.

*PROTAC® is a registered trademark of Arvinas. In this article, PROTAC specifically refers to the abbreviation of Proteolysis-Targeting Chimera as therapeutic modalities.

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