PII-041 - A CHEMICAL BIOLOGY STRATEGY FOR PREDICTING OATP1B-TYPE TRANSPORTER-MEDIATED DRUG-DRUG INTERACTION (DDI) LIABILITIES

M. Nepal¹, G. Taylor², T. Drabison², E. Ahmed², A. Jakate², M. Wu², Z. Lin², A. Sparreboom², B. Peterson², S. Hu²; ¹The Ohio State University, OH, United States, ²The Ohio State University.

Background: Organic anion transporting polypeptides 1B1 and 1B3 (OATP1B) are pivotal hepatic drug transporters. Inhibiting OATP1B can lead to defective elimination, elevated plasma concentrations, and therapy-related side effects. Although some endogenous OATP1B substrates have been explored as potential biomarkers for clinical evaluation of OATP1B-mediated DDIs, the inhibitory potential of most prescription drugs remains unknown. This study aims to explore the OATP1B inhibitory potential of approved drugs utilizing small molecule screening approaches and validate their potential for DDIs in translationally relevant rodent models.

Methods: A Prestwick library of 1520 FDA-approved drugs were screened using OATP1B3-overexpressing HEK293 cells and PB-Gly-Taxol as a fluorescent substrate of OATP1B. Compounds inhibiting OATP1B activity by >50% were further characterized with fluorescent and radiolabeled substrates, 8-FCA and EbG. The hit compound was selected for in vivo biomarker confirmation and DDI potential evaluation with the OATP1B substrate pravastatin in WT and OATP1A/1B KO mice. Pharmacokinetic profiling was evaluated with LC-MS/MS and calculated with WinNonlin software (Version 8.1).

Results: Forty-one drugs were initially identified, and 10 were further assessed based on physicochemical properties. Four drugs, including rifapentine, pyrvinium pamoate, dihydroergotamine, and dipyridamole, exhibited the greatest inhibition potency against all three OATP1Bs and were confirmed with the secondary substrate, EbG. Rifapentine was identified as the most potent inhibitor with IC50 < 1 µM. In vivo studies showed a >3-fold increase in the biomarker CDCA-24G compared to vehicle-treated mice following a clinically relevant dose of rifapentine (20 mg/kg, oral), and DDI studies with pravastatin revealed a 2.3-fold AUC increase in wild-type mice but not in OATP1A/1B KO mice.

Conclusion: This study systematically evaluated the DDI potential of FDA-approved drugs and identified rifapentine as a novel potent OATP1Bs inhibitor both in vitro and in vivo. This unbiased approach addresses a knowledge deficit linking this process to clinically relevant DDIs and could ultimately lead to future evaluations of refined treatment strategies in patients by avoiding harmful DDIs.