Study On The Stereoselective Pharmacokinetics Of Budesonide In Humans

Background Budesonide (BUD) is a non-halogenated glucocorticoid with high local anti-inflammatory. It is used as a mixture of22R and22S epimers for the topical treatment of asthma, rhinitis, and inflammatory bowel disease. To the best of our knowledge, no study on pharmacokinetics of22R-BUD inhaled via Turbuhaler(?) and stereoselective pharmacokinetics of BUD epimers after oral administration have been reported.Objective First, a highly sensitive and selective high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was to be developed for determination of22R-BUD in human plasma. And then the method should be applied in a pharmacokinetic study of22R-BUD inhaled via Turbuhaler(?) in healthy Chinese volunteers. Second, an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was to be developed for simultaneous determination of BUD epimers in human plasma. And the method should be applied in a stereoselective pharmacokinetic study of BUD controlled-release capsules after oral administration in healthy Chinese volunteers.Method The epimers of BUD were extracted from plasma using n-hexane/dichloromethane/isopropanol (2:1:0.1, v/v/v) under alkaline conditions, using BUD-d8as internal standard. For the determination of22R-BUD, chromatographic separation was achieved on a Capcell Pak C18MG column (100mm x4.6mm,5μm) using acetonitrile/5mM ammonium acetate (75:25, v/v) as the mobile phase. For the simultaneous determination of BUD epimers, baseline separation was obtained within7min on an Acquity UPLC BEH C18(50x2.1mm,1.7μm) column using an isocratic mobile phase consisting of acetonitrile/5mM ammonium acetate/acetic acid (29:71:0.142, v/v/v) at a flow rate of0.7mL/min. The Qtrap5500triple quadrupole mass spectrometric detection was performed in a multiple reaction monitoring mode using the m/z489→357transition for BUD epimers and the m/z497→357transition for the internal standard BUD-d8epimers.Results Calibration curve was linear over the concentration range of2.0-1000pg/mL for22R-BUD, and the lower limit of quantification was2.0pg/mL. The method was successfully applied in a pharmacokinetic study of22R-BUD inhaled via Turbuhaler(?) in humans. The results showed that between160and640μg,22R-BUD appeared to have dose-proportional pharmacokinetics.Calibration curves were linear over the concentration ranges of5.0-500and5.0-3000pg/mL for22R-BUD and22S-BUD, respectively. The lower limit of quantification was5.0pg/mL for both epimers. The method was successfully applied in a pharmacokinetic study of BUD controlled-release capsules in humans. Consistent differences in the pharmacokinetics of the22R and22S epimers were observed, the AUC(0-∝) of22S-BUD was approximately six times higher than that of22R-BUD, and the22S-/22R-BUD ratio of total body clearance was0.17.Conclusion This study developed fast, selective, and sensitive LC-MS/MS and UHPLC-MS/MS methods for the determination of22R-BUD and simultaneous determination of22R-and22S-BUD in human plasma, respectively. The former has been successfully applied in a phannacokinetic study of22R-BUD inhaled via Turbuhaler(?) and the latter has been applied in a stereoselective pharmacokinetic study of BUD controlled-release capsules. There were consistent differences in the pharmacokinetics of the two epimers after oral administration.