Sum C Y, Yacobi A
J Pharm Sci. 1984 Aug;73(8):1177-9. doi: 10.1002/jps.2600730842.
Esmolol is an ultra-short-acting beta-blocker currently in Phase II clinical trials. The ester functionality in esmolol results in rapid metabolism of the beta-blocker into an acidic metabolite and methanol. Dichloromethane was used to denature blood esterases and quantitatively extract esmolol from the blood. A deuterated analogue of esmolol was selected as the internal standard, and both compounds were chromatographed as the trimethylsilyl derivatives. Blood levels of esmolol were quantitated by gas chromatography-mass spectrometry with selective-ion monitoring, focusing on specific ions corresponding to esmolol and the internal standard. The lower limit of sensitivity of the assay was 2.5 ng/mL. Using the assay, blood samples from a dose-ranging study in humans were analyzed for concentrations of esmolol. Steady-state blood levels of esmolol after intravenous infusion rates of 40, 100, 200, 300, 450, and 650 micrograms/kg/min were 0.202, 0.464, 0.977, 1.31, 1.92, and 2.97 micrograms/mL of blood. The elimination t1/2 and total body clearance were estimated to be approximately 10 min and 220 mL/kg/min, respectively. The high clearance of esmolol suggested that metabolism by blood esterase(s) was the primary determinant of the duration of action of the drug.
艾司洛尔是一种超短效β受体阻滞剂，目前正处于II期临床试验阶段。艾司洛尔中的酯官能团导致该β受体阻滞剂迅速代谢为酸性代谢物和甲醇。二氯甲烷用于使血液酯酶变性并从血液中定量提取艾司洛尔。选择艾司洛尔的氘代类似物作为内标，两种化合物均作为三甲基硅烷基衍生物进行色谱分析。通过气相色谱 - 质谱联用的选择性离子监测对艾司洛尔的血药浓度进行定量，重点关注与艾司洛尔和内标对应的特定离子。该测定法的灵敏度下限为2.5 ng/mL。使用该测定法，对人体剂量范围研究中的血样进行了艾司洛尔浓度分析。静脉输注速率为40、100、200、300、450和650微克/千克/分钟后，艾司洛尔的稳态血药浓度分别为0.202、0.464、0.977、1.31、1.92和2.97微克/毫升血液。消除半衰期和全身清除率估计分别约为10分钟和220毫升/千克/分钟。艾司洛尔的高清除率表明血液酯酶的代谢是该药物作用持续时间的主要决定因素。
