Studies On Stereoselective Pharmacokinetics And Metabolites Of Bambuterol And Salbutamol In Chinese Subjects

β₂-agonists are currently the most widely used bronchodilator in clinical practice, and bambuterol belongs to its long-acting kind, salbutamol belongs to its short-acting kind. Both of them are chiral drugs. In this thesis, a chiral LC-MS/MS method has been developed for determination of bambuterol and salbutamol in human biological samples, respectively. The stereoselectivity pharmacokinetics of bambuterol and salbutamol in human has been studied. What’s more, metabolites of salbutamol in vivo has been studied using UPLC/Q-TOF MS, and the preliminary metabolic pathways of salbutamol has been identified. Following is the main content:1. A chiral LC-MS/MS method has been developed for simultaneous determination of bambuterol, its two major metabolites “monocarbamate bambuterol” and “terbutaline” in human plasma for the first time. Plasma samples were prepared by liquid-liquid extraction. The calibration curves for bambuterol enantiomers were linear in the range of 25.00²500 pg/m L, and for monocarbamate bambuterol and terbutaline enantiomers were linear in the range of 50.00⁵000 pg/m L. The precision, matrix effect and other indexes all accorded with the analysis criteria. A stereoselectivity pharmacokinetics of bambuterol, monocarbamate bambuterol and terbutaline in human after oral administration with 10 mg bambuterol tablets has been studied. The results show that stereoselective metabolism existed in the metabolic process of bambuterol, monocarbamate bambuterol and terbutaline enantiomers in human, and the body has stereoselective to these drugs.2. A chiral LC-MS/MS method has been developed for determination of salbutamol in human plasma and urine samples. Biological samples were prepared by liquid-liquid extraction. The calibration curves for salbutamol enantiomers were linear in the range of 0.1000¹0.00 ng/m L. The precision, matrix effect and other indexes all accorded with the analysis criteria. A stereoselectivity pharmacokinetics and bioequivalence of salbutamol in human after oral administration with 2.4 mg R-salbutamol tablets, 2.4 mg R-salbutamol granules and 4.8 mg Rac-salbutamol tablets has been studied. The results show that the R-salbutamol of the three pharmaceutical preparation are bioequivalent. The effect of analysis conditions on the PH, temperature and time has been studied for the first time, and the results show that the chiral conversion rate of salbutamol enantiomers are 0.0% under the existing analysis conditions（PH 11.25, 26℃, 1 h）.3. A UPLC/Q-TOF MS method has been developed for metabolites identification of salbutamol in human biological samples. Urine samples were directly injected after high speed centrifugation, plasma and feces samples were prepared by protein precipitation. The metabolites of salbutamol in human after oral administration with 2.4 mg R-salbutamol tablets has been studied, and 15 metabolites（11 from urine, 3 from plasma, 4 from feces） were found, including 10 metabolites that never been reported before. The phase I metabolism of salbutamol mainly contains oxidation, reduction, dealkylation; The phase II metabolism of salbutamol mainly contains glucuronidation and sulfation.