Back to Search
Start Over
Effects of Bardoxolone Methyl on Hepatic Enzymes in Patients with Type 2 Diabetes Mellitus and Stage 4 CKD.
- Source :
-
Clinical and translational science [Clin Transl Sci] 2021 Jan; Vol. 14 (1), pp. 299-309. Date of Electronic Publication: 2020 Sep 03. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)
- Subjects :
- Aged
Alanine Transaminase genetics
Alanine Transaminase metabolism
Aspartate Aminotransferases genetics
Aspartate Aminotransferases metabolism
Diabetes Mellitus, Type 2 blood
Diabetes Mellitus, Type 2 drug therapy
Diabetes Mellitus, Type 2 physiopathology
Female
Gene Expression Regulation, Enzymologic drug effects
Glomerular Filtration Rate drug effects
Glomerular Filtration Rate physiology
Humans
Kidney drug effects
Kidney physiopathology
Kidney Failure, Chronic blood
Kidney Failure, Chronic etiology
Kidney Failure, Chronic physiopathology
Liver drug effects
Liver enzymology
Male
Middle Aged
NF-E2-Related Factor 2 metabolism
Oleanolic Acid pharmacology
Oleanolic Acid therapeutic use
Alanine Transaminase blood
Aspartate Aminotransferases blood
Diabetes Mellitus, Type 2 complications
Kidney Failure, Chronic drug therapy
Oleanolic Acid analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1752-8062
- Volume :
- 14
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical and translational science
- Publication Type :
- Academic Journal
- Accession number :
- 32860734
- Full Text :
- https://doi.org/10.1111/cts.12868