Authentic Bosutinib Inhibits Triiodothyronine Transport by Monocarboxylate Transporter 8

BraunDoreen,; Schweizer, Ulrich

doi:10.1089/thy.2013.0660

Cited by 11 publications

(5 citation statements)

References 2 publications

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“…The bosutinib isomer 1 was originally unintentionally sold to the research community (also to us) as authentic bosutinib by several vendors (http://www. pkcpharma.com/TwoOrMoreBosutinibs.html) (Levinson and Boxer, 2012;Beeharry et al, 2013;Braun and Schweizer, 2014). The bosutinib results of the recent study correspond well with the inhibitory characteristics of bosutinib isomer 1 in our study.…”

Section: Discussionsupporting

confidence: 89%

In Vitro Assessment of Time-Dependent Inhibitory Effects on CYP2C8 and CYP3A Activity by Fourteen Protein Kinase Inhibitors

2014

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Previous studies have shown that several protein kinase inhibitors are time-dependent inhibitors of cytochrome P450 (CYP) 3A. We screened 14 kinase inhibitors for time-dependent inhibition of CYP2C8 and CYP3A. Amodiaquine N-deethylation and midazolam 19-hydroxylation were used as marker reactions for CYP2C8 and CYP3A activity, respectively. A screening, IC 50 shift, and mechanismbased inhibition were assessed with human liver microsomes. In the screening, bosutinib isomer 1, crizotinib, dasatinib, erlotinib, gefitinib, lestaurtinib, nilotinib, pazopanib, saracatinib, sorafenib, and sunitinib exhibited an increased inhibition of CYP3A after a 30-min preincubation with NADPH, as compared with no preincubation. Axitinib and vandetanib tested negative for time-dependent inhibition of CYP3A and CYP2C8, and bosutinib was the only inhibitor causing timedependent inhibition of CYP2C8. The inhibitory mechanism by bosutinib was consistent with weak mechanism-based inhibition, and its inactivation variables, inhibitor concentration that supports half-maximal rate of inactivation (K I ) and maximal inactivation rate (k inact ), were 54.8 mM and 0.018 1/min. As several of the tested inhibitors were reported to cause mechanism-based inactivation of CYP3A4 during the progress of this work, detailed experiments with these were not completed. However, lestaurtinib and saracatinib were identified as mechanism-based inhibitors of CYP3A. The K I and k inact of lestaurtinib and saracatinib were 30.7 mM and 0.040 1/min, and 12.6 mM and 0.096 1/min, respectively. Inhibition of CYP2C8 by bosutinib was predicted to have no clinical relevance, whereas therapeutic lestaurtinib and saracatinib concentrations were predicted to increase the plasma exposure to CYP3A-dependent substrates by ‡2.7-fold. The liability of kinase inhibitors to affect CYP enzymes by time-dependent inhibition may have long-lasting consequences and result in clinically relevant drug-drug interactions.

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Section: Discussionsupporting

confidence: 89%

In Vitro Assessment of Time-Dependent Inhibitory Effects on CYP2C8 and CYP3A Activity by Fourteen Protein Kinase Inhibitors

2014

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“…The tricyclic antidepressant desipramine inhibits both MCT8 and MCT10 (194), whereas the flavonolignan silychristin appears to be a specific inhibitor of MCT8 (79). Moreover, several tyrosine kinase inhibitors have been found to interfere with MCT8 and MCT10 function through noncompetitive Review inhibition (195)(196)(197)(198). Although not as extensively studied as short MCT8, the long isoform of human MCT8 also efficiently transports iodothyronines (80,199).…”

Section: Substrate Specificity and Transport Directionmentioning

confidence: 99%

Thyroid Hormone Transporters

et al. 2019

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Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease.

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“…Desipramine, an inhibitor of LeuT, also inhibits MCT8 and MCT10, despite the fact that MCT belong to the MFS, while LeuT belongs to the LeuT family of transporters [65]. Moreover, several tyrosine kinase inhibitors interfere with the TH axis by non-competitive inhibition of MCT8 [66,67]. …”

Section: Th Transportersmentioning

confidence: 99%

Structure and Function of Thyroid Hormone Plasma Membrane Transporters

et al. 2014

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Thyroid hormones (TH) cross the plasma membrane with the help of transporter proteins. As charged amino acid derivatives, TH cannot simply diffuse across a lipid bilayer membrane, despite their notorious hydrophobicity. The identification of monocarboxylate transporter 8 (MCT8, SLC16A2) as a specific and very active TH transporter paved the way to the finding that mutations in the MCT8 gene cause a syndrome of psychomotor retardation in humans. The purpose of this review is to introduce the current model of transmembrane transport and highlight the diversity of TH transmembrane transporters. The interactions of TH with plasma transfer proteins, T₃ receptors, and deiodinase are summarized. It is shown that proteins may bind TH owing to their hydrophobic character in hydrophobic cavities and/or by specific polar interaction with the phenolic hydroxyl, the aminopropionic acid moiety, and by weak polar interactions with the iodine atoms. These findings are compared with our understanding of how TH transporters interact with substrate. The presumed effects of mutations in MCT8 on protein folding and transport function are explained in light of the available homology model.

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Authentic Bosutinib Inhibits Triiodothyronine Transport by Monocarboxylate Transporter 8

Cited by 11 publications

References 2 publications

In Vitro Assessment of Time-Dependent Inhibitory Effects on CYP2C8 and CYP3A Activity by Fourteen Protein Kinase Inhibitors

In Vitro Assessment of Time-Dependent Inhibitory Effects on CYP2C8 and CYP3A Activity by Fourteen Protein Kinase Inhibitors

Thyroid Hormone Transporters

Structure and Function of Thyroid Hormone Plasma Membrane Transporters

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