Drug Design, Development and Therapy (Jul 2020)
Effects of Dexmedetomidine on the Pharmacokinetics of Dezocine, Midazolam and Its Metabolite 1-Hydroxymidazolam in Beagles by UPLC-MS/MS
Abstract
Wei Zhou,1,2 Shuang-long Li,3 Ti Zhao,3 Le Li,3 Wen-bin Xing,3 Xiang-jun Qiu,3 Wei Zhang1 1The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China; 2Nanyang City Central Hospital, Nanyang 473009, People’s Republic of China; 3School of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaCorrespondence: Wei ZhangThe First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of ChinaEmail [email protected] QiuSchool of Basic Medicine, Henan University of Science and Technology, Luoyang 471023, People’s Republic of ChinaEmail [email protected]: We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles.Materials and Methods: Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 μg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 μg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg.Results: Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements.Conclusion: The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug–drug interaction should be paid attention to when the drugs were used in combination.Keywords: dexmedetomidine, dezocine, midazolam, 1-hydroxymidazolam, pharmacokinetics, drug–drug interactions
