Study on the determination and chiral inversion of R-salbutamol in human plasma and urine by liquid chromatography-tandem mass spectrometry.
The chiral inversion has been a concerned issue during the research and development of a chiral drug. In this study, a sensitive chiral liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for determination of salbutamol enantiomers in human plasma and urine. The chiral inversion mechanism of R-salbutamol was fully investigated for the first time by studying the effects of physicochemical factors, including pH, temperature and time. A fitted model to predict the chiral inversion ratio of R-salbutamol was proposed using a Box-Behnken design. All the samples were separated on an Astec Chirobiotic T column and detected by a tandem mass spectrometer in multiple reaction monitoring mode. Lower limit of quantification of 0.100ng/mL was achieved under the optimized conditions. The method was fully validated and successfully applied to the clinical pharmacokinetic study of R-salbutamol in healthy volunteers. Chiral inversion of R-salbutamol to S-salbutamol has been detected in urine samples. The results indicated that pH and temperature were two dominant factors that caused the chiral inversion of R-salbutamol, which should be taken into consideration during the analysis of chiral drugs. The chiral inversion of R-salbutamol determined in this study was confirmed resulted from the gastric acid in stomach rather than caused by the analysis conditions. Moreover, the calculated results of the fitted model matched very well with the enantioselective pharmacokinetic study of R-salbutamol, and the individual difference of the chiral inversion ratio of R-salbutamol was related to the individual gastric environment. On the basis of the results, this study provides important and concrete information not only for the chiral analysis but also for the metabolism research of chiral drugs.
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China; Pre-incubator for Innovative Drugs and Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China.
Ting
T
Zhou
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China; Pre-incubator for Innovative Drugs and Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China.
Jing
J
Zeng
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China; Pre-incubator for Innovative Drugs and Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China.
Shan
S
Liu
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China; Pre-incubator for Innovative Drugs and Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China.
Ting
T
Zhao
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China; Pre-incubator for Innovative Drugs and Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China.
Jie
J
Wu
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China; Pre-incubator for Innovative Drugs and Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China.
Wenshi
W
Lai
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China.
Mingzhi
M
He
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China.
Beining
B
Xu
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China.
Shanshan
S
Qu
Keypharma Biomedical Inc., Songshan Lake Science & Technology Industry Park, Dongguan 523808, China.
Ling
L
Xu
School of Bioscience and Bioengineering, South China University of Technology, Guangzhou, 510006, China; Pre-incubator for Innovative Drugs and Medicine, South China University of Technology, Guangzhou 510006, China; Guangdong Provincial Key Laboratory of Fermentation and Enzyme Engineering, South China University of Technology, Guangzhou 510006, China. Electronic address: went@scut.edu.cn.
Wen
W
Tan
D000318:Adrenergic beta-Agonists / Q000097:blood* / Q000652:urine*; D000420:Albuterol / Q000097:blood* / Q000652:urine*; D002853:Chromatography, Liquid / Q000379:methods*; D006801:Humans; D057230:Limit of Detection; D013237:Stereoisomerism; D053719:Tandem Mass Spectrometry / Q000379:methods*
D000318:Adrenergic beta-Agonists; D000420:Albuterol
Chiral inversion; Clinical pharmacokinetics; LC–MS/MS; R-salbutamol; Stereoselective determination