S. N. Gupta,1 C. Hsueh,1 S. Yee,1 D. Weitz,2 K. Mertsch,2 W. Brain,3 K. Giacomini1; 1UCSF, Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, San Francisco, CA, 2Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany, 3R&D DSAR / Drug Disposition FFSciences, Schools of Pharmacy and Medicine, Frankfurt, Germany

BACKGROUND: OATP1B1 (SLCO1B1) and OATP1B3 (SLCO1B3) are important drug transporters in the liver that mediate clinically relevant drug-drug interactions. Safety biomarkers are needed to evaluate the potential for new drugs to inhibit such transporters. The goal of this study was to identify potential biomarkers for OATP1B3.
METHODS: Published genome-wide studies showing significant associations between genetic variants in the SLCO1B1/SLCO1B3 locus and serum levels of various metabolites were used to identify potential endogenous substrates of OATP1B1 and OATP1B3 (PMID: 24816252). An inhibitor screening of all metabolites was performed in HEK293 cells stably expressing OATP1B3 using a fluorescent compound, 6-carboxyfluorescein diacetate (6-CFDA), as a probe. The ability of the following metabolites to reduce the uptake of 6-CFDA by OATP1B3 was evaluated: L-alanine, uridine, tyrosine, sodium taurolithocholate (STLCA), taurolithocholic acid 3-sulfate disodium salt (TLCA3), taurocholic acid, sodium glycochenodeoxycholate (NaGCDC), niacinamide, and adenosine.
RESULTS: 6-CFDA exhibited excellent uptake characteristics (e.g. ~10-fold uptake at 10 min in OATP1B3 expressing HEK293 cells vs. empty vector cells, p < 0.01). Of the metabolites tested, NaGCDC, STLCA, and TLCA3 significantly reduced the uptake of 6-CFDA by 75% (IC50: 3.4 µM), 98% (IC50: 0.4 µM), and 74% (IC50: 0.8 µM), respectively (p<0.01).
CONCLUSION: We identified NaGCDC, STLCA, and TLCA3 as potent inhibitors of OATP1B3, which suggests that they may be potential substrates and biomarkers of OATP1B3. By inference, these compounds may be useful in monitoring OATP1B3 transport activity, clinically. Further studies are needed to evaluate the utility of the compounds to serve as biomarkers.