Effects of Dexmedetomidine on the Pharmacokinetics of Dezocine, Midazolam and Its Metabolite 1-Hydroxymidazolam in Beagles by UPLC-MS/MS

• Published in: Drug design, development and therapy Vol. 14; pp. 2595 - 2605
• Main Authors: Zhou, Wei, Li, Shuang-Long, Zhao, Ti, Li, Le, Xing, Wen-Bin, Qiu, Xiang-Jun, Zhang, Wei
• Format: Journal Article
• Language: English
• Published: New Zealand Taylor & Francis Ltd 01.01.2020; Dove; Dove Medical Press
• Subjects: 1-hydroxymidazolam; Accuracy; Acetonitrile; Anesthesia; Animals; Benzodiazepines; Breastfeeding & lactation; Bridged Bicyclo Compounds, Heterocyclic - blood; Bridged Bicyclo Compounds, Heterocyclic - metabolism; Bridged Bicyclo Compounds, Heterocyclic - pharmacokinetics; Calibration; Chromatography, High Pressure Liquid; Clinical medicine; dexmedetomidine; Dexmedetomidine - blood; Dexmedetomidine - metabolism; Dexmedetomidine - pharmacokinetics; dezocine; Diazepam; Dogs; Drug dosages; Drug interaction; Drug interactions; drug-drug interactions; Female; Formic acid; Injection; Intravenous administration; Linearity; Male; Metabolism; Metabolites; Midazolam; Midazolam - analogs & derivatives; Midazolam - blood; Midazolam - metabolism; Midazolam - pharmacokinetics; Narcotics; Original Research; Pharmaceuticals; Pharmacokinetics; Pharmacology; Plasma; Positive ions; Tandem Mass Spectrometry; Tetrahydronaphthalenes - blood; Tetrahydronaphthalenes - metabolism; Tetrahydronaphthalenes - pharmacokinetics; United States > US; pharmacokinetics; dexmedetomidine; midazolam; 1-hydroxymidazolam; dezocine; drug–drug interactions
• ISSN: 1177-8881; 1177-8881
• DOI: 10.2147/DDDT.S254055

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. 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. 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. 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.