In Vitro and in Vivo Drug Metabolism Analysis of BPI-460372, a Covalent TEAD1/3/4 Inhibitor

摘要: Background: BPI-460372 is an orally available, covalent, irreversible small molecule inhibitor of the tranObjective: This study aimed to determine the cytochrome P450 (CYP) phenotyping, metabolic stability, in vitro and in vivo metabolic profile of BPI-460372.
Methods: The CYP phenotyping and metabolic stability were assessed by measuring the depletion of substrate. The metabolic profile in hepatocytes, rats, and dog plasma was analyzed using ultra-high performance liquid chromatography combined with orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).
Results: BPI-460372 was mainly metabolized by CYP2D6, CYP3A4, and CYP1A2. BPI-460372 exhibited low clearance in human, monkey, and rat hepatocytes, while moderate clearance in dog and mouse hepatocytes. A total of 10 metabolites were identified in five species of hepatocytes, and no human unique metabolite was detected. In rat plasma and dog plasma, the primary metabolites were M407 (BPI-460430) and M423 (BPI-460456), respectively. The two metabolites were quantitatively determined in rat and dog plasma in pharmacokinetic and toxicological studies. The major metabolic sites were 2-fluoro acrylamide, and major metabolic pathways in hepatocytes, rats, and dog plasma involved oxidative defluorination, hydration, glutathione conjugation, hydrolysis, cysteine conjugation and N-acetyl cysteine conjugation. β-lyase pathway contribute to the metabolism of BPI-460372 in rats to a certain degree.
Conclusion: This study elucidated the metabolism of BPI-460372 and provided a basis for pharmacokinetic and toxicological species selection, human pharmacokinetics prediction, clinical co-administration limitations, and possible metabolic pathways in humans.