Effects of Bardoxolone Methyl on Hepatic Enzymes in Patients with Type 2 Diabetes Mellitus and Stage 4 CKD

Autor: Megan O'Grady, Colin J. Meyer, Michel Jadoul, Scott A. Reisman, James H. Lewis, Pablo E. Pergola, Geoffrey A. Block, Angie Goldsberry, Glenn M. Chertow, Deborah A. Ferguson, W. Christian Wigley, Melanie P. Chin
Přispěvatelé: UCL - SSS/IREC/NEFR - Pôle de Néphrologie, UCL - (SLuc) Service de néphrologie
Rok vydání: 2020
Předmět:
Male
030213 general clinical medicine
Kidney
030226 pharmacology & pharmacy
chemistry.chemical_compound
0302 clinical medicine
Bardoxolone methyl
General Pharmacology
Toxicology and Pharmaceutics
education.field_of_study
lcsh:Public aspects of medicine
General Neuroscience
Alanine Transaminase
Biological activity
Articles
General Medicine
Middle Aged
Liver
Female
Glomerular Filtration Rate
medicine.medical_specialty
NF-E2-Related Factor 2
Bilirubin
Population
Renal function
Reference range
digestive system
Article
Gene Expression Regulation
Enzymologic
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Internal medicine
medicine
Humans
Aspartate Aminotransferases
Oleanolic Acid
education
Aged
business.industry
Research
lcsh:RM1-950
Type 2 Diabetes Mellitus
lcsh:RA1-1270
digestive system diseases
lcsh:Therapeutics. Pharmacology
Endocrinology
Diabetes Mellitus
Type 2
chemistry
Kidney Failure
Chronic
Stage 4 chronic kidney disease
business
Zdroj: Clinical and Translational Science, Vol 14, Iss 1, Pp 299-309 (2021)
Clinical and translational science, Vol. 14, no. 1, p. 299-309 (2021)
Clinical and translational science, Vol. 14, no.1, p. 299-309 (2021)
Clinical and Translational Science
ISSN: 1752-8062
1752-8054
Popis: In a multinational placebo‐controlled phase III clinical trial in 2,185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, treatment with the Nrf2 activator bardoxolone methyl increased estimated glomerular filtration rate, a measure of kidney function, but also resulted in increases in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase. These increases in liver enzyme level(s) were maximal after 4 weeks of treatment and reversible, trending back toward baseline through week 48. Total bilirubin concentrations did not increase, and no cases met Hy’s Law criteria, although two subjects had ALT concentrations that exceeded 10 × the upper limit of the population reference range leading to discontinuation of treatment. Animal and cell culture experiments suggested that the increases in ALT and AST induced by bardoxolone methyl may be related to its pharmacological activity. Bardoxolone methyl significantly induced the mRNA expression of ALT and AST isoforms in cultured cells. Expression of ALT and AST isoforms in liver and kidney also positively correlated with Nrf2 status in mice. Overall, these data suggest that the increases in ALT and AST observed clinically were, at least in part, related to the pharmacological induction of aminotransferases via Nrf2 activation, rather than to any intrinsic form of hepatotoxicity.
Databáze: OpenAIRE
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