Large inter-individual variability in pharmacokinetics of dexmedetomidine and its two major N-glucuronides in adult intensive care unit patients

Publication date: Available online 16 July 2019Source: Journal of Pharmaceutical and Biomedical AnalysisAuthor(s): Mengbi Yang, Andrew H.W. Tse, Anna Lee, Gavin M. Joynt, Zhong ZuoAbstractDexmedetomidine (DMTD), an α2-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 N3-glucuronide of dexmedetomidine (DG1) and N1-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 fro...
Source: Journal of Pharmaceutical and Biomedical Analysis - Category: Drugs & Pharmacology Source Type: research