Quantitative Analyses Of Dronedarone And Its Active Metabolite SR35021 In Plasma And Applications

Objective: To develop and validate a liquid chromatography–tandem mass spectrometry (LC–MS/MS) method for the simultaneous determination of dronedarone and its metabolite SR35021 in plasma to study the relative bioavailability and pharmacokinetic in Beagle dog and health human.Methods: For determination of the dog plasma concentration of dronedarone and its metabolite SR35021, an aliquot of 50μL plasma was treated by protein precipitation with acetonitrile, dronedarone, SR35021 and internal standard (tolvaptan) were separated on a Capcell Pak C18 MG column using acetonitrile-methanol-5 mmol/L ammonium acetate-acetic acid (55: 10: 35: 0.07, v/v/v/v) as the mobile phase. For determination of the human plasma concentration of dronedarone and SR35021, an aliquot of 50μL plasma was treated by protein precipitation with acetonitrile, dronedarone, SR35021 and internal standard (amiodarone) were separated on a Capcell Pak C18 MG column using acetonitrile-5 mmol/L ammonium acetate-acetic acid as mobile phase by gradient elution. A tandem mass spectrometer equipped with atmospheric pressure chemical ionization source was used as detector and operated in the positive ion mode. Quantification was performed using multiple reaction monitoring (MRM) of the transitions m/z 557→m/z 100, m/z 501→m/z 114, m/z 449→m/z 252 and m/z 646→m/z 100 for dronedarone, SR35021, IS (tolvaptan) and IS (amiodarone), respectively.Results: The linear ranges of the calibration curves for dronedarone and SR35021 were both 0.200 ~ 200 ng/mL. The lower limit of quantitation (LLOQ) of dronedarone and SR35021 were both 0.200 ng/mL. The intra–day and inter–day precision (RSD) of dronedarone and SR35021 were both less than 15%. The accuracy (RE) was within–15 ~ 15%.After an oral administration of dronedarone hydrochloride tablet (400 mg) (Reference and Test) to Beagle dogs,the mean Tmax values of dronedarone and SR35021 were both approximately 1.8 h, and the values of plasma terminal half–life of dronedarone and ST35021 were approximately 6 h and 3 h, respectively. The exposure of dronedarone is 8 times more than SR35021. Based on the dronedarone and SR35021 AUC0?t values, the relative bioavailability of dronedarone and SR35021 (test formulation) in dogs were estimated to be 96.9% and 104%, respectively.Food can affect the absorption of dronedarone in Beagle dog. Relative to the fasted state, the Cmax and AUC0-t of dronedarone were increased by a factor of 6.16 and 6.54, respectively. The Cmax and AUC0-t of SR35021 were increased by a factor of 3.39 and 3.95, respectively.The difference in pharmacokinetic parameters between the species is profound. After an oral administration of dronedarone hydrochloride tablet (400 mg) to healthy volunteers under fed conditons,the mean Tmax values of dronedarone and SR35021 were approximately 4 h and 4.5 h, respectivelt. And the values of plasma terminal half–life of dronedarone and ST35021 were approximately 16 h and 22 h, respectively. The exposure of dronedarone was lower than that of SR35021.The exposure of SR35021 in human was significantly higher than that in Beagle dog. The exposure of SR35021 was slightly higher than dronedarone in human.Conclusion: The validated liquid chromatographic?tandem mass spectrometric methods were sensitive, selective, rapid and suitable for pharmacokinetic study of dronedarone hydrochloride tablet.