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Competitive Inhibition of Organic Anion Transporting Polypeptide 1c1-Mediated Thyroxine Transport by the Fenamate Class of Nonsteroidal Antiinflammatory Drugs

Department of Pharmacy Practice and Pharmaceutical Sciences (D.E.W., D.D.S., G.W.A.) and Departments of Chemistry and Biochemistry (J.N.R.) and Biochemistry and Molecular Biology (L.R.D.), University of Minnesota Duluth, Duluth, Minnesota 55812

Address all correspondence and requests for reprints to: Grant W. Anderson, 232 Life Science, 1110 Kirby Drive, Duluth, Minnesota 55812. E-mail: ander163{at}umn.edu.

Organic anion transporting polypeptide (Oatp) 1c1 is a high-affinity T₄ transporter with narrow substrate specificity expressed at the blood-brain barrier. A transport model using cells overexpressing Oatp1c1 was created to identify novel Oatp1c1 substrates and inhibitors. Rat Oatp1c1 was cloned and stably expressed in human embryonic kidney 293 cells. Oatp1c1-transfected human embryonic kidney 293 cells transported ¹²⁵I-labeled T₄ in a time-dependent manner that was completely abolished in the presence of excess unlabeled T₄. Next, various compounds, including inhibitors of thyroid hormone uptake, were screened for inhibitory effects on Oatp1c1-mediated T₄ uptake. Phenytoin (64%), indocyanine green (17%), fenamic acid (68%), diclofenac (51%), and meclofenamic acid (33%) all reduced T₄ uptake by Oatp1c1 when assayed at concentrations of 10 µM. Dose-response assays for the fenamic acids, iopanoic acid, indocyanine green, and phenytoin revealed IC₅₀ values for Oatp1c1 T₄ uptake below or near the blood plasma levels after therapeutic doses. Further kinetic assays and reciprocal plot analyses demonstrated that the fenamic acid diclofenac inhibited in a competitive manner. Finally, microvessels were isolated from adult rat brain and assessed for T₄ uptake. Ten micromolar of fenamate concentrations inhibited T₄ microvessel uptake with a similar hierarchical inhibition profile [fenamic acid (43%), diclofenac (78%), and meclofenamic acid (85%)], as observed for Oatp1c1 transfected cells. Oatp1c1 is expressed luminally and abluminally in the blood-brain barrier endothelial cell, and exhibits bidirectional transport capabilities. Together, these data suggest that Oatp1c1 transports fenamates into, and perhaps across, brain barrier cells.

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				D. E. Westholm, D. R. Salo, K. J. Viken, J. N. Rumbley, and G. W. Anderson The Blood-Brain Barrier Thyroxine Transporter Organic Anion-Transporting Polypeptide 1c1 Displays Atypical Transport Kinetics Endocrinology, November 1, 2009; 150(11): 5153 - 5162. [Abstract] [Full Text] [PDF]