Tyrosine kinase inhibitors noncompetitively inhibit MCT8-mediated iodothyronine transport.
BACKGROUND
Tyrosine kinase inhibitors (TKI) are used for the treatment of various cancers. Case reports and clinical trials have reported abnormal thyroid function tests (TFT) after treatment with sunitinib, imatinib, sorafenib, dasatinib, and nilotinib. An increased requirement for levothyroxine was reported in thyroidectomized patients during TKI treatment.


OBJECTIVE
We hypothesized that abnormal TFT are compatible with inhibition of thyroid hormone (TH) transporters and subsequently reduced pituitary-TH feedback. Monocarboxylate transporter 8 (MCT8) is a TH transmembrane transporter in brain, pituitary, and other organs. MCT8 mutation leads to abnormal TFT in patients and respective mouse models. We tested whether TKI are able to inhibit MCT8-mediated TH uptake into cells.


METHODS
Madin-Darby-canine kidney (MDCK1) cells stably expressing human MCT8 were exposed in vitro to TKI at increasing concentrations, and MCT8-mediated [(125)I]T(3) uptake and efflux were measured. The mode of inhibition was determined.


RESULTS
TKI exposure dose-dependently inhibited MCT8-dependent T(3) and T(4) uptake. IC(50) values for sunitinib, imatinib, dasatinib, and bosutinib ranged from 13-38 μm, i.e. similar to the Michaelis-Menten constant K(m) for T(3) and T(4), 4 and 8 μm, respectively. Kinetic experiments revealed a noncompetitive mode of inhibition for all TKI tested.


CONCLUSIONS
Partial inhibition by TKI of pituitary or hypothalamic TH feedback may increase TSH or increase the levothyroxine requirement of thyroidectomized patients. It is still possible that other mechanisms contribute to TKI-mediated impairments of TFT, e.g. altered metabolism of TH. Bosutinib was not previously reported to alter TFT.
Institut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Doreen
D
Braun
Theo D
TD
Kim
Philipp
P
le Coutre
Josef
J
Köhrle
Jerome M
JM
Hershman
Ulrich
U
Schweizer
D000818:Animals; D001549:Benzamides; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D002478:Cells, Cultured; D002986:Clinical Trials as Topic; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000494:pharmacology; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000652:urine; D027501:Monocarboxylic Acid Transporters / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000077210:Sunitinib; D027981:Symporters; D013974:Thyroxine / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine
D001549:Benzamides; D007211:Indoles; D007457:Iodine Radioisotopes; D027501:Monocarboxylic Acid Transporters; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D013974:Thyroxine; D000077210:Sunitinib