Pharmacokinetics and Metabolism of ARV-393, a BCL6 PROTAC Degrader, in Dogs by UPLC-MS/MS and UPLC-Q-Exactive
Qiuyan Wang1, Rui Li2, Huiying Zhang1
1Department of Pharmacy, Xuzhou Central Hospital Affiliated Southeast University, Xuzhou, Jiangsu Province, China.
Abstract:
ARV-393 is a novel PROTAC designed to degrade B-cell lymphoma 6. To support its further development, it is necessary to disclose the pharmacokinetic and metabolism profiles. To achieve this goal, in this study, a simple and sensitive UPLC-MS/MS method was developed for the quantification of ARV-393 and a UPLC-Q-Exactive Orbitrap-HRMS method was utilized to identify its metabolites in dog plasma. After acetonitrile-mediated protein precipitation, the sample was separated on a Waters ACQUITY BEH C18 column (50 mm × 2.1 mm, 1.7 μm). The mobile phase consisted of 2 mM of ammonium acetate and acetonitrile, each containing 0.1% formic acid, delivered at 0.4 mL/min. The analyte and internal standard were quantified using the transitions of m/z 898.2 → 398.2 and m/z 724.4 → 396.2, respectively. The method demonstrated excellent linearity over the concentration range of 1.0-1000 ng/mL (r > 0.998). The validated method was successfully applied to a pharmacokinetic study of ARV-393 in dogs. The results indicated that ARV-393 exhibits low clearance and favorable bioavailability (64.7%). Four metabolites were tentatively identified by accurate mass and fragment ions. The proposed metabolic pathways include hydroxylation and hydrolysis. This work provides an overview of the pharmacokinetic and metabolism of ARV-393, laying a foundation for further development.
