Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication

Wang, Ling; Wang, Shaoming; Qi, Juan; Yu, Rongguo; Zhuang, Jie; Bo-yang, Zhuang; Lou, Yongming; Ruan, Junshan; Ye, Hong; Lin, Fangfang

doi:10.1080/17512433.2018.1510312

Cited by 8 publications

(10 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…According to the well stirred liver model, liver blood flow and not enzyme activity is the main determinant of clearance for high extraction ratio drugs. This reasoning is supported by experimental work by Kohli et al 22 and Wang et al, 23 who observed no influence of CYP2A6 metabolizer status on dexmedetomidine pharmacokinetics.…”

Section: Dexmedetomidine Elicits Nonlinear Kineticsmentioning

confidence: 62%

Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

et al. 2021

View full text Add to dashboard Cite

Background Numerous pharmacokinetic models have been published aiming at more accurate and safer dosing of dexmedetomidine. The vast majority of the developed models underpredict the measured plasma concentrations with respect to the target concentration, especially at plasma concentrations higher than those used in the original studies. The aim of this article was to develop a dexmedetomidine pharmacokinetic model in healthy adults emphasizing linear versus nonlinear kinetics. Methods The data of two previously published clinical trials with stepwise increasing dexmedetomidine target-controlled infusion were pooled to build a pharmacokinetic model using the NONMEM software package (ICON Development Solutions, USA). Data from 48 healthy subjects, included in a stratified manner, were utilized to build the model. Results A three-compartment mamillary model with nonlinear elimination from the central compartment was superior to a model assuming linear pharmacokinetics. Covariates included in the final model were age, sex, and total body weight. Cardiac output did not explain between-subject or within-subject variability in dexmedetomidine clearance. The results of a simulation study based on the final model showed that at concentrations up to 2 ng · ml–1, the predicted dexmedetomidine plasma concentrations were similar between the currently available Hannivoort model assuming linear pharmacokinetics and the nonlinear model developed in this study. At higher simulated plasma concentrations, exposure increased nonlinearly with target concentration due to the decreasing dexmedetomidine clearance with increasing plasma concentrations. Simulations also show that currently approved dosing regimens in the intensive care unit may potentially lead to higher-than-expected dexmedetomidine plasma concentrations. Conclusions This study developed a nonlinear three-compartment pharmacokinetic model that accurately described dexmedetomidine plasma concentrations. Dexmedetomidine may be safely administered up to target-controlled infusion targets under 2 ng · ml–1 using the Hannivoort model, which assumed linear pharmacokinetics. Consideration should be taken during long-term administration and during an initial loading dose when following the dosing strategies of the current guidelines. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

show abstract

Section: Dexmedetomidine Elicits Nonlinear Kineticsmentioning

confidence: 62%

Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Unfortunately, there is a lack of information on personalized medicine involving dexmedetomidine. Previous studies have demonstrated that no significant pharmacokinetic differences were observed among genetic variations in CYP2A6 (Utkarsh et al, ; Wang et al, ). However, population differences exist in the frequencies of different CYP2A6 alleles in Asian and Caucasian populations (Carter et al, ; Utkarsh et al, ).…”

Section: Resultsmentioning

confidence: 94%

“…Because of the paucity of substrates, the significance of genetic variations in CYP2A6 has not been well understood. Findings from other studies have shown that the gene variations in CYP2A6 had no significant influence on the pharmacokinetics of dexmedetomidine (Utkarsh et al, ; Wang et al, ). However, certain factors including inadequate samples, a combination of medications and the complex pathophysiological conditions still impact the results.…”

Section: Introductionmentioning

confidence: 93%

Quantitative ultra‐high‐performance liquid chromatography–tandem mass spectrometry for determination of dexmedetomidine in pediatric plasma samples: Correlation with genetic polymorphisms

Guan

Wei

et al. 2019

Biomedical Chromatography

View full text Add to dashboard Cite

Dexmedetomidine is an important sedative agent administered as premedication to achieve procedural sedation in children. To describe the correlation between the genetic state and the concentration of dexmedetomidine, it is necessary to develop a specific, time-saving and economical method for detection of dexmedetomidine in plasma samples. In this work, an ultra-high-performance liquid chromatography (UHPLC)-tandem mass spectrometry method has been established and validated for detection of dexmedetomidine in plasma from pediatric population. After a simple liquid-liquid extraction with an organic solution, the analytes were separated on an ACQUITY BEH C 18 column (2.1 mm × 50 mm, 1.7 μm particle size) by gradient elution with the mobile phase of acetonitrile and 1‰ aqueous formic acid (flow rate 0.3 mL min −1 ). Mass spectrometry measurements were performed under the positive selected reaction monitoring and the mass transitions monitored were m/z 201.3 → 95.1, 204.2 → 98.0 for dexmedetomidine and deuterated medetomidine (internal standard), respectively. Validation of the method based on China Food and Drug Administration guidelines showed acceptable selectivity. The UHPLC method employed a stable isotope-labeled internal standard, showed good specificity and was successfully used to detect dexmedetomidine in plasma samples from 260 pediatric patients. A subsequent application of this method to a pharmacogenetic study was also described. Importantly, this is the first study to report the correlation between CYP2A6 rs835309 activity and concentration of dexmedetomidine.

show abstract

“…Mycophenolate mofetil was administered from POD 14–21 (daily doses of 2 g). The details of the immunosuppression protocol and standard surgical techniques used in this study have been described previously [ 24 , 25 , 26 ]. We do not routinely remove the spleen and preserve the middle hepatic vein for donors.…”

Section: Methodsmentioning

confidence: 99%

Sedative and Immunosuppressive Effects of Dexmedetomidine in Transplantation

et al. 2021

View full text Add to dashboard Cite

Dexmedetomidine, an α2-adrenergic receptor agonist, is used as an anti-anxiety medication. It exerts a cholinergic effect, thereby reducing the release of tumor necrosis factor alpha (TNF-α). We hypothesized that the use of dexmedetomidine as a sedative agent in transplantation would also protect allografts. We examined our patients who underwent living donor liver transplantation. Subsequently, we generated a series of mouse models to investigate the effect of dexmedetomidine on sedation-based tolerance post transplantation. A total of 49 liver recipients were enrolled in this study, of which 23 (47%) were administered dexmedetomidine through 24 h infusion on postoperative day 1. A trend toward the improvement of hepatocyte injury along with better liver function was observed in the dexmedetomidine-treated group during the first postoperative week. In animal models, dexmedetomidine inhibited the proliferation of CD4+ and CD8+ T cells and TNF-α production in a dose-dependent manner. We used dexmedetomidine to treat skin-transplanted mice and observed a significantly prolonged graft survival in mice that were administered a higher dose of dexmedetomidine. Our results revealed that dexmedetomidine exerts a dual effect of sedation and immunosuppression. This light-sedation approach will not only make patients calmer in the intensive care unit but also protect allografts from injury.

show abstract

Impact of CYP2A6 gene polymorphism on the pharmacokinetics of dexmedetomidine for premedication

Abstract: In Chinese patients pretreated with dexmedetomidine, T was consistent with that published, but T, V and Cl were lower. It was unnecessary to consider the mutation when developing the precision regimen of dexmedetomidine.

Cited by 8 publications

References 36 publications

Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

Dexmedetomidine Clearance Decreases with Increasing Drug Exposure: Implications for Current Dosing Regimens and Target-controlled Infusion Models Assuming Linear Pharmacokinetics

Quantitative ultra‐high‐performance liquid chromatography–tandem mass spectrometry for determination of dexmedetomidine in pediatric plasma samples: Correlation with genetic polymorphisms

Sedative and Immunosuppressive Effects of Dexmedetomidine in Transplantation

Contact Info

Product

Resources

About