School of Pharmacy, The Chinese University of Hong Kong, Hong Kong.
Department of Anaesthesia and Intensive Care, The Chinese University of Hong Kong, Hong Kong.
J Pharm Biomed Anal. 2019 Oct 25;175:112777. doi: 10.1016/j.jpba.2019.07.025. Epub 2019 Jul 16.
Dexmedetomidine (DMTD), an α-adrenoceptor agonist, is commonly used for sedation and analgesia in intensive care unit (ICU) patients. The primary plasma metabolites of DMTD are its direct N-glucuronides, namely N-glucuronide of dexmedetomidine (DG1) and N-glucuronide of dexmedetomidine (DG2), accounting for 41% of DMTD metabolism in healthy volunteers. Since variations on the extent of N-glucuronidation could be one of the key factors contributing to the high interpatient differences of DMTD pharmacokinetics in ICU patients and its subsequent sedative effect. In order to fully evaluate the N-glucuronidation of DMTD in ICU patients, the current study aimed to develop a LC/MS/MS method to simultaneously quantify DMTD and its two major N-glucuronides, DG1 and DG2, in plasma samples and describe their pharmacokinetics in adult ICU patients. Solid-phase extraction cartridges were used to effectively extract DMTD, DG1 and DG2 from 0.4 mL plasma with the internal standard tolazoline. The method was applied in determining the pharmacokinetic profiles of DMTD, DG1, and DG2 in nine ICU patients (mean ± SD admission severity of illness APACHE II score 23 ± 5) receiving dexmedetomidine infusion for 667 to 3518 min. Under the optimized LC/MS/MS conditions, no endogenous interference from blank plasma was observed. The linear range was 25-5000 pg/mL for DMTD, 50-5000 pg/mL for DG1, and 56-2800 pg/mL for DG2 with good linearity (r ranges: 0.997-0.999, 0.993-0.999, and 0.993-0.998 for DMTD, DG1 and DG2 respectively). The precision, accuracy and the stability of DMTD, DG1, and DG2 at their quality control concentrations complied with Food and Drug Administration bioanalytical criteria. The assay was applied in determining the pharmacokinetic profiles of DMTD, DG1, and DG2 in nine ICU patients. The range of AUC/AUC (from 0.40 to 2.20) and AUC/AUC (from 0.15 to 2.02) suggested large inter-patient differences in the glucuronidation of DMTD. The mean AUC ratio between total glucuronides and DMTD in ICU patients receiving infusions (2.09, range 0.55-4.16) appeared lower than the reported value in healthy volunteers receiving bolus intravenous injection (2.86). This description of the pharmacokinetics of DMTD, DG1, and DG2 in ICU patients is novel and suggests that pathophysiological changes in critically ill patients may have potential to decrease the glucuronidation of DMTD.
右美托咪定（DMTD）是一种α-肾上腺素受体激动剂，常用于重症监护病房（ICU）患者的镇静和镇痛。DMTD 的主要血浆代谢物是其直接 N-葡萄糖醛酸苷，即右美托咪定 N-葡萄糖醛酸苷（DG1）和右美托咪定 N-葡萄糖醛酸苷（DG2），占健康志愿者 DMTD 代谢的 41%。由于 N-葡萄糖醛酸化程度的差异可能是 ICU 患者 DMTD 药代动力学个体间差异及其随后镇静作用的关键因素之一。为了充分评估 ICU 患者 DMTD 的 N-葡萄糖醛酸化，本研究旨在开发一种 LC/MS/MS 方法，同时定量测定血浆中 DMTD 及其两种主要 N-葡萄糖醛酸苷 DG1 和 DG2，并描述其在成年 ICU 患者中的药代动力学特征。采用固相萃取小柱，以内标托拉唑啉从 0.4 mL 血浆中有效提取 DMTD、DG1 和 DG2。该方法应用于确定 9 例 ICU 患者（平均入科严重程度 APACHE II 评分 23±5）接受右美托咪定输注 667 至 3518 分钟后 DMTD、DG1 和 DG2 的药代动力学特征。在优化的 LC/MS/MS 条件下，空白血浆无内源性干扰。DMTD 的线性范围为 25-5000 pg/mL，DG1 为 50-5000 pg/mL，DG2 为 56-2800 pg/mL，线性良好（r 范围分别为 0.997-0.999、0.993-0.999 和 0.993-0.998 对于 DMTD、DG1 和 DG2）。DMTD、DG1 和 DG2 在其质控浓度下的精密度、准确度和稳定性符合食品和药物管理局生物分析标准。该方法应用于确定 9 例 ICU 患者 DMTD、DG1 和 DG2 的药代动力学特征。AUC/AUC（0.40-2.20）和 AUC/AUC（0.15-2.02）的范围表明 DMTD 葡萄糖醛酸化的个体间差异较大。接受输注的 ICU 患者总葡萄糖醛酸化物与 DMTD 的平均 AUC 比值（2.09，范围 0.55-4.16）似乎低于接受静脉推注的健康志愿者的报告值（2.86）。这一描述 ICU 患者 DMTD、DG1 和 DG2 的药代动力学特征是新颖的，表明危重病患者的病理生理变化可能降低 DMTD 的葡萄糖醛酸化。
