Quantification of Thyromimetic Sobetirome Concentration in Biological Tissue Samples

Devereaux, Jordan; Ferrara, Skylar J.; Scanlan, Thomas S.

doi:10.1007/978-1-4939-7902-8_16

Cited by 4 publications

(7 citation statements)

References 48 publications

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“…65 In contrast to the other thyromimetic agents, sobetirome is able to penetrate towards blood-brain barrier and has potential neurological effects. 66 It has a half-life below an hour and has potentially lower selectivity towards TR-β receptors, 10-fold selectivity. 66 Major tissue effects of sobetirome is directed towards kidneys and liver.…”

Section: Sobetirome (Gc-1)mentioning

confidence: 99%

Thyroid hormone Beta receptor agonists for treatment of kidney disease: A promising agent?

Çöpür

Yavuz

Kanbay

2023

Eur J Clin Investigation

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Background: Chronic kidney disease is a common disorder affecting a significant portion of the adult population with high mortality and morbidity. Obesity and hyperlipidemia are prevalent in chronic kidney disease, and they may trigger fat accumulation in renal parenchyma and eventually fatty kidney. Chronic kidney disease and fatty kidney are also strongly associated with nonalcoholic fatty liver disease. Because they both lead to detrimental effects on organ function, they both need to be treated effectively to improve the outcome. Aim:In this narrative review, we have hypothesized that thyroid hormone beta receptor agonists, a novel drug group, may potentially be beneficial in the management of chronic kidney disease due to its promising outcomes among patients with nonalcoholic fatty liver disease, a condition sharing multiple common underlying pathophysiological mechanisms. Results and Conclusion:Thyroid hormone beta receptors are abundantly expressed in liver and kidney tissues, while both nonalcoholic fatty liver disease and chronic kidney disease share various similar pathophysiological mechanisms and triggers. Therefore, thyroid hormone beta receptor agonists may become a promising tool in the management of patients with chronic kidney disease.

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Section: Sobetirome (Gc-1)mentioning

confidence: 99%

Thyroid hormone Beta receptor agonists for treatment of kidney disease: A promising agent?

Çöpür

Yavuz

Kanbay

2023

Eur J Clin Investigation

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“…The oral bioavailability of Sob-AM2 is 20% in mice, while that of sobetirome is >90% (Meinig et al, 2019). To confirm that chow administration of either drug provides the anticipated sobetirome levels in vivo, sobetirome concentrations in serum and brain were measured in mice administered chow for 12 weeks at doses of 80 µg/kg sobetirome or 84 µg/kg Sob-AM2 (Devereaux et al, 2018;Placzek et al, 2016;Placzek and Scanlan, 2015). Serum levels of sobetirome were lower after Sob-AM2 administration, and brain levels of sobetirome were similar from the two different drugs ( Figure S3).…”

Section: Sob-am2 Lowered Peripheral and Central Vlcfas After Oral Admmentioning

confidence: 99%

“…The samples were extracted in acetonitrile (75 μl) with vortexing. Debris was removed with centrifugation at 10,000 x g for 15 minutes, and the supernatant was analyzed via LC-MS/MS (Devereaux et al, 2018;Placzek et al, 2016). Whole or half brain was homogenized at 200 mg tissue/ml in water using a BeadMill 24 (ThermoScientific) with 3 metal beads per 2 ml tube.…”

Section: Lc-ms/ms Quantification Of Sobetiromementioning

confidence: 99%

Pharmacological complementation remedies an inborn error of lipid metabolism

Hartley

Shokat

DeBell

et al. 2019

Preprint

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X-linked adrenoleukodystrophy (X-ALD) is a genetic disease involving loss of function of the peroxisomal transporter ABCD1, resulting in an inappropriate increase in very long chain fatty acid (VLCFA) concentrations throughout the body. Elevated levels of VLCFAs in the central nervous system (CNS) cause demyelination and axonal degeneration, leading to severe neurological deficits. Sobetirome, a potent thyroid hormone agonist, and other thyromimetics have been shown to lower VLCFA levels. In this study, two pharmacological strategies for enhancing the effects of thyromimetics in the brain were tested. First, a CNS-selective thyromimetic prodrug was used to increase thyromimetic drug exposure in the CNS. Second, thyroid hormone and the thyromimetic were co-administered to increase total thyroid hormone agonism in the CNS. These strategies lowered VLCFAs by up to 60% in the periphery. In the brain and spinal cord, C26/C22 was lowered by 15-20% and C26-LPC by 25-30% in the brain and ~40% in the spinal cord. Co-administration of thyroid hormone with sobetirome led to enhanced VLCFA lowering in the periphery compared to sobetirome alone but did not produce greater lowering in the CNS. The extent of lowering in the brain was limited by a mechanistic threshold related to slow turnover kinetics, which increased thyroid hormone action could not overcome. These findings provide evidence that CNS-penetrating thyromimetics can lower VLCFAs in peripheral organs in addition to the brain and spinal cord, thereby correcting the lipid abnormality associated with X-ALD. Keywordsthyroid hormone, thyromimetics, prodrugs, X-linked adrenoleukodystrophy, demyelination, very long chain fatty acids, myelin lipids, CNS lipids, inborn error of metabolism

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“…See also Figure S2 and Tables S1 and S4. chow for 12 weeks at equimolar doses of 80 mg/kg sobetirome or 84 mg/kg Sob-AM2 (Devereaux et al, 2018;Placzek et al, 2016;Placzek and Scanlan, 2015). Serum levels of sobetirome were lower after Sob-AM2 administration (Figure 2C), and brain levels of sobetirome were similar from the two different drugs (Figure 2D).…”

Section: Introductionmentioning

confidence: 97%