Synthesis of 14C-Meglumine Salicylate and Its Disposition in Humans after Oral Administration

Farid, Nagy A.; Born, Gordon S.; Kessler, Wayne V.; Russell, Henry T.; Shaw, Stanley M.; Lange, Winthrop E.

doi:10.1002/jps.2600660419

Cited by 1 publication

(1 citation statement)

References 12 publications

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“…1 Pharmacokinetic analysis in mice revealed that meglumine delivered orally at high doses can achieve measurable serum bioavailability in comparison with earlier studies in which lower doses of meglumine were delivered to humans or rats. 11,21 This result is consistent with earlier reports demonstrating a pharmacodynamic impact of high-dose oral meglumine on levels of SNF1-AMP-activated protein kinase (AMPK) related kinase (also known as NUAK2), a derivative of the master metabolic kinase AMPK. 1 Together, these results form a preclinical pharmacological foundation to help advance our understanding of this substanceʼs potential medicinal properties.…”

Section: Discussionsupporting

confidence: 91%

Preclinical study of the long‐range safety and anti‐inflammatory effects of high‐dose oral meglumine

Manley

Bravo‐Nuevo

Minton

et al. 2019

J of Cellular Biochemistry

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Meglumine is a methylamino derivative of sorbitol that is an approved drug excipient. Recent preclinical studies suggest that administration of high-dose oral meglumine can exert beneficial medicinal effects to treat diabetes, obesity, and fatty liver disease (NAFLD/nonalcoholic steatohepatitis [NASH]). Here we address gaps in knowledge about the pharmacology and toxicology of this substance administered at high concentrations to explore its medicinal potential. We observed that high-dose meglumine limited secretion of proinflammatory cytokines and cell adhesion molecules from activated human THP-1 or murine RAW264.7 monocytes. Preclinical pharmacokinetic analysis in Swiss mice confirmed that meglumine was orally available. Informed by this data, oral doses of 18 to 75 mM meglumine were administered ad libitum in the drinking water of Sprague-Dawley rats and two cohorts of C57BL/6 mice housed in different vivariums. In a 32-week study, urinary isoprostane levels trended lower in subjects consistent with the possibility of antiinflammatory effects. In full lifespan studies, there was no detrimental effect on longevity. Heart function evaluated in C57BL/6 mice using an established noninvasive cardiac imaging system showed no detrimental effects on ejection fraction, fractional shortening, left ventricle function or volume, and cardiac output in mice up to 15-month old, with a potential positive trend in heart function noted in elderly mice consistent with earlier reported benefits on muscle stamina. Finally, in a transgenic model of inflammation-associated skin carcinogenesis, the incidence, number, and growth of skin tumors trended lower in subjects receiving meglumine. Overall, the evidence obtained illustrating the long-range safety of high-dose oral meglumine support the rationale for its evaluation as a low-cost modality to limit diabetes, hypertriglyceridemia, and NAFLD/NASH. K E Y W O R D Sdrug discovery, preclinical pharmacology, preclinical toxicology

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