Screening for drugs potentially interfering with MCT8-mediated T transport in vitro identifies dexamethasone and some commonly used drugs as inhibitors of MCT8 activity.

Background: Monocarboxylate transporter 8 (MCT8) is the first thyroid hormone transporter that has been linked to a human disease. Besides genetic alterations other factors might impair MCT8 activity.

Aim: This study aimed at investigating whether some common drugs having a structural similarity with TH and/or whose treatment is associated with thyroid function test abnormalities, or which behave as antagonists of TH action can inhibit MCT8-mediated T transport.

Methods: [I]T uptake and efflux were measured in COS-7 cells transiently transfected with hMCT8 before and after exposure to increasing concentrations of hydrocortisone, dexamethasone, prednisone, prednisolone, amiodarone, desethylamiodarone, dronedarone, buspirone, carbamazepine, valproic acid, and L-carnitine. The mode of inhibition was also determined.

Results: Dexamethasone significantly inhibited T uptake at 10 μM; hydrocortisone reduced T uptake only at high concentrations, i.e. at 500 and 1000 μM; prednisone and prednisolone were devoid of inhibitory potential. Amiodarone caused a reduction of T uptake by MCT8 only at the highest concentrations used (44% at 50 μM and 68% at 100 μM), and this effect was weaker than that produced by desethylamiodarone and dronedarone; buspirone resulted a potent inhibitor, reducing T uptake at 0.1-10 μM. L-Carnitine inhibited T uptake only at 500 mM and 1 M. Kinetic experiments revealed a noncompetitive mode of inhibition for all compounds. All drugs inhibiting T uptake did not affect T release.

Conclusion: This study shows a novel effect of some common drugs, which is inhibition of T transport mediated by MCT8. Specifically, dexamethasone, buspirone, desethylamiodarone, and dronedarone behave as potent inhibitors of MCT8.