Large inter-individual variability in pharmacokinetics of dexmedetomidine and its two major N-glucuronides in adult intensive care unit patients
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AbstractDexmedetomidine (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 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 (r2 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 AUCDG1/AUCDMTD (from 0.40 to 2.20) and AUCDG2/AUCDMTD (from 0.15 to 2.02) suggested large inter-patient differences in the glucuronidation of DMTD. The mean AUC0-∞ 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.
Acceptance Date15/07/2019
All Author(s) ListMengbi Yang, Andrew H.W. Tse, Anna Lee, Gavin M.Joynt, Zhong Zuo
Journal nameJournal of Pharmaceutical and Biomedical Analysis
Volume Number175
Article number112777
LanguagesEnglish-United States
KeywordsDexmedetomidine, Clinical pharmacokinetic, Glucuronide, Metabolism, Intensive care patient, LC/MS/MS

Last updated on 2020-22-11 at 02:37