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- Title
Evidence for cytochrome P450 3A4‐mediated metabolic activation of SCO‐267.
- Authors
Li, Cui; Li, Xiaokun; Fan, Ali; He, Ning; Wu, Dongmei; Yu, Hongyan; Wang, Kun; Jiao, Weijie; Zhao, Xu
- Abstract
SCO‐267 is a potent G‐protein‐coupled receptor 40 agonist that is undergoing clinical development for the treatment of type 2 diabetes mellitus. The current work was undertaken to investigate the bioactivation potential of SCO‐267 in vitro and in vivo. Three SCO‐267‐derived glutathione (GSH) conjugates (M1–M3) were found both in rat and human liver microsomal incubations supplemented with GSH and nicotinamide adenine dinucleotide phosphate. Two GSH conjugates (M1–M2) together with two N‐acetyl‐cysteine conjugates (M4–M5) were detected in the bile of rats receiving SCO‐267 at 10 mg/kg. The identified conjugates suggested the generation of quinone‐imine and ortho‐quinone intermediates. CYP3A4 was demonstrated to primarily catalyze the bioactivation of SCO‐267. In addition, SCO‐267 concentration‐, time‐, and NADPH‐dependently inactivated CYP3A in human liver microsomes using testosterone as a probe substrate, along with KI and kinact values of 4.91 μM and 0.036 min−1, respectively. Ketoconazole (a competitive inhibitor of CYP3A) displayed no significant protective effect on SCO‐267‐induced CYP3A inactivation. However, inclusion of GSH showed significant protection. These findings revealed that SCO‐267 undergoes a facile CYP3A4‐catalyzed bioactivation with the generation of quinone‐imine and ortho‐quinone intermediates, which were assumed to be involved in SCO‐267 induced CYP3A inactivation. These findings provide further insight into the bioactivation pathways involved in the generation of reactive, potentially toxic metabolites of SCO‐267. Further studies are needed to evaluate the influence of SCO‐267 metabolism on the safety of this drug in vivo.
- Subjects
CYTOCHROME P-450; BIOTRANSFORMATION (Metabolism); NICOTINAMIDE adenine dinucleotide phosphate; TYPE 2 diabetes; LIVER microsomes
- Publication
Biopharmaceutics & Drug Disposition, 2024, Vol 45, Issue 1, p30
- ISSN
0142-2782
- Publication type
Article
- DOI
10.1002/bdd.2381