Core shell stationary phase for a novel separation of some COVID-19 used drugs by UPLC-MS/MS Method: Study of grapefruit consumption impact on their pharmacokinetics in rats

Abstract

A sensitive and selective UPLC-MS/MS method was developed for the synchronized determination of four drugs used in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), namely, azithromycin, apixaban, dexamethasone, and favipiravir in rat plasma. using a Poroshell 120 EC-C18 column (50 mm × 4.6 mm, 2.7 m) with a high-resolution ESI tandem mass spectrometer detection with multiple reaction monitoring. We used an Agilent Poroshell column, which is characterized by a stationary phase based on non-porous core particles. With a remarkable improvement in the number of theoretical plates and low column backpressure. In addition, the developed method was employed in studying the potential food-drug interaction of grapefruit juice (GFJ) with the selected drugs which affects their pharmacokinetics in rats. The LC-MS/MS operated in positive and negative ionization mode using two internal standards: moxifloxacin and chlorthalidone, respectively. Liquid- liquid extraction of the cited drugs from rat plasma was accomplished using diethyl ether: dichloromethane (70:30, v/v). The analytes were separated using methanol: 0.1 % formic acid in water (95: 5, v/v) as a mobile phase in isocratic mode of elution pumped at a flow rate of 0.3 mL/min. A detailed validation of the bio-analytical method was performed in accordance with US-FDA and EMA guidelines.Concerning the in vivo pharmacokinetic study, the statistical significance between the results of the test groups receiving GFJ along with the cited drugs and the control group was assessed demonstrating that GFJ increased the plasma concentration of azithromycin, apixaban, and dexamethasone. Accordingly, this food–drug interaction requires cautious ingestion of GFJ in patients using (SARS-CoV-2) medications as it can produce negative effects in the safety of the drug therapy. A potential drug–drug interaction is also suggested between those medications requiring a suitable dose adjustment.