Bioanalytical method validation, biopharmaceutical and pharmacokinetic evaluation of GSK-650394, a serum- and glucocorticoid-regulated kinase 1 inhibitor

초록

GSK-650394 is an inhibitor of serum-and glucocorticoid-regulated kinase 1 that dis-plays potency for treating cancer, hypertension, cardiovascular and neuronal diseases, such as Parkinson's disease. However, the biopharmaceutical properties and pharmacokinetics of GSK-650394 have not been studied extensively. Also, there are currently no bioanalytical assays available for this new drug candidate. In this study, we developed a simple and sensitive liquid chromatography-tandem mass spectrometry method to quantify GSK-650394 in rat plasma and validated its selectivity, linearity, accuracy and precision, sensitivity, matrix effects, extraction recovery, and stability, following the United States Food and Drug Administration guidelines. In vitro studies showed the biopharmaceutical properties of GSK-650394, including its low solubility in water and simulated gastrointestinal fluids, passive transport in Caco-2 cell monolayers, high plasma protein binding, and primary metabolism by glucuronide conjugation in the small intestine and liver of rats. Following intravenous administration (2 mg/kg) to rats, GSK-650394 exhibited low total clearance (11.18 +/- 1.28 mL/min/kg) and volume of distribution at steady-state (346.1 +/- 120.6 mL/kg). Following oral administration (2, 5, and 10 mg/kg) to rats, GSK-650394 under-went enterohepatic circulation, with low bioavailability (-9%). The insignificant difference in

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