Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 110, Issue 2, Pages 914-924Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.xphs.2020.10.009
Keywords
Organic anion transporters; Organic anion transporting polypeptides; Wnt inhibitors; Molecular regulation
Funding
- University of Sydney Equity fellowship, Australia
- Wepon-University of Sydney post-graduate scholarship
- Young Talent's Subsidy Project in Science and Education of the Department of Public Health of Jiangsu Province [QNRC2016627]
- Six talent peaks project in Jiangsu Province [WSW-047]
- Six-one Scientific Research Project [LGY2019087]
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This study evaluated the regulatory actions of Wnt inhibitors on human renal Organic anion transporters and Organic anion transporting polypeptides, showing that these inhibitors significantly decrease the activities and membrane expression of multiple transporters. The findings suggest that Wnt inhibitors may have unexpected effects on drug entry into cells.
The Wnt/beta-catenin signaling pathway is dysregulated in diseases and Wnt inhibitors like PRI-724 are in clinical development. This study evaluated the regulatory actions of PRI-724 and other Wnt inhibitors on the transport activity of human renal Organic anion transporters (OATs) and Organic anion transporting polypeptides (OATPs). The substrate uptake by OAT4 and OATP2B1 was markedly decreased by PRI-724 (V-max/K-m: similar to 26% and similar to 17% of corresponding control), with less pronounced decreases in OAT1, OAT3 and OAT1A2. PRI-724 decreased the plasma membrane expression of inhibited OATs/OATPs but didn't affect their total cellular expression. Two model Wnt inhibitors - FH535 and 21H7 - were also tested in comparative studies. Like PRI-724, they also strongly decreased the activities and membrane expression of multiple OATs/OATPs. In contrast, FH535 didn't affect the substrate uptake by organic cation transporters. In control studies, the EGFR inhibitor lapatinib did not inhibit the function of some OATs/OATPs. Together these findings suggest that Wnt inhibitors selectively modulate the function of multiple organic anions transporters, so their clinical use may have unanticipated effects on drug entry into cells. These findings are pertinent to current clinical trials that have been designed to understand the safety and efficacy of new Wnt inhibitor drugs. (c) 2020 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
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