Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

Dijkman, Sven C. van; Cock, Pieter De; Smets, Koenraad; Decaluwe, Wim; Smits, Anne; Allegaert, Karel; Walle, Johan Vande; Paepe, Peter De; Pasqua, Oscar Della

doi:10.1007/s00228-019-02708-y

Cited by 16 publications

(16 citation statements)

References 40 publications

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“…The clearance of A small pilot study in term neonates examined scaled pharmacokinetic models that were obtained by applying allometry and maturation to already published data. The clearance of intravenous DEX using this method was up to 20% higher than in previously published reports, with a clearance of 2.29 L/h in a full-term infant and higher in those born earlier [4].…”

Section: Updates On Pharmacologycontrasting

confidence: 57%

Dexmedetomidine: What’s New for Pediatrics? A Narrative Review

Mahmoud

Barbi

Mason

2020

JCM

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Over the past few years, despite the lack of approved pediatric labelling, dexmedetomidine’s (DEX) use has become more prevalent in pediatric clinical practice as well as in research trials. Its respiratory-sparing effects and bioavailability by various routes are only some of the valued features of DEX. In recent years the potential organ-protective effects of DEX, with the possibility for preserving neurocognitive function, has put it in the forefront of clinical and bench research. This comprehensive review focused on the pediatric literature but presents relevant, supporting adult and animal studies in order to detail the recent growing body of literature around the pharmacology, end-organ effects, organ-protective effects, alternative routes of administration, synergetic effects, and clinical applications, with considerations for the future.

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Section: Updates On Pharmacologycontrasting

confidence: 57%

Dexmedetomidine: What’s New for Pediatrics? A Narrative Review

Mahmoud

Barbi

Mason

2020

JCM

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“…Dexmedetomidine is a highly selective α 2-adrenoceptor agonist with sedative, antianxiety, sympathetic, and analgesic effects [ 1 ]. Dexmedetomidine is metabolized by glucuronization and CYP2A6 hydroxylation and then excreted almost completely as a metabolite in urine [ 5 , 6 ]. Dexmedetomidine is a strong inhibitor of cytochrome CYP450 enzyme [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…After intravenous administration, dexmedetomidine quickly distributes beyond total body water. Dexmedetomidine is metabolized by glucuronization and CYP2A6 hydroxylation and then excreted almost completely as a metabolite in urine [5,6]. Body weight, liver damage, plasma albumin, and cardiac output may have significant effects on the pharmacokinetics of dexmedetomidine [3].…”

Section: Introductionmentioning

confidence: 99%

Effects of Dexmedetomidine on the Pharmacokinetics of Parecoxib and Its Metabolite Valdecoxib in Beagles by UPLC-MS/MS

Guo

et al. 2020

BioMed Research International

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A sensitive and reliable ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of parecoxib and its metabolite valdecoxib in beagles. The effects of dexmedetomidine on the pharmacokinetics of parecoxib and valdecoxib in beagles were studied. The plasma was precipitated by acetonitrile, and the two analytes were separated on an Acquity UPLC BEH C18 column (2.1 mm×50 mm, 1.7 μm); the mobile phase was acetonitrile and 0.1% formic acid with gradient mode, and the flow rate was 0.4 mL/min. In the negative ion mode, the two analytes and internal standard (IS) were monitored by multiple reaction monitoring (MRM), and the mass transition pairs were as follows: m/z 369.1→119.1 for parecoxib, m/z 313.0→118.0 for valdecoxib, and m/z 380.0→316.0 for celecoxib (IS). Six beagles were designed as a double cycle self-control experiment. In the first cycle, after intramuscular injection of parecoxib 1.33 mg/kg, 1.0 mL blood samples were collected at different times (group A). In the second cycle, the same six beagles were intravenously injected with 2 μg/kg dexmedetomidine for 7 days after one week of washing period. On day 7, after intravenous injection of 2 μg/kg dexmedetomidine for 0.5 hours, 6 beagle dogs were intramuscularly injected with 1.33 mg/kg parecoxib, and blood samples were collected at different time points (group A). The concentration of parecoxib and valdecoxib was detected by UPLC-MS/MS, and the main pharmacokinetic parameters were calculated by DAS 2.0 software. Under the experimental conditions, the method has a good linear relationship for both analytes. The interday and intraday precision was less than 8.07%; the accuracy values were from -1.20% to 2.76%. Cmax of parecoxib in group A and group B was 2148.59±406.13 ng/mL and 2100.49±356.94 ng/mL, t1/2 was 0.85±0.36 h and 0.85±0.36 h, and AUC0‐t was 2429.96±323.22 ng·h/mL and 2506.38±544.83 ng·h/mL, respectively. Cmax of valdecoxib in group A and group B was 2059.15±281.86 ng/mL and 2837.39±276.78 ng/mL, t1/2 was 2.44±1.55 h and 2.91±1.27 h, and AUC0‐t was 4971.61±696.56 ng·h/mL and 6770.65±453.25 ng·h/mL, respectively. There was no significant change in the pharmacokinetics of parecoxib in groups A and B. Cmax and AUC0−∞ of valdecoxib in group A were 37.79% and 36.19% higher than those in group B, respectively, and t1/2 was increased from 2.44 h to 2.91 h. Vz/F and CLz/F were correspondingly reduced, respectively. The developed UPLC-MS/MS method for simultaneous determination of parecoxib and valdecoxib in beagle plasma was specific, accurate, rapid, and suitable for the pharmacokinetics and drug-drug interactions of parecoxib and valdecoxib. Dexmedetomidine can inhibit the metabolism of valdecoxib in beagles and increase the exposure of valdecoxib, but it does not affect the pharmacokinetics of parecoxib.

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“…DEX is metabolised by glucuronidation and CYP2A6 hydroxylation and subsequently excreted in urine almost exclusively as metabolite. 8,9 Dezocine (DEZ, Figure 1A) is a marketed opioid analgesic of the benzomorphan group. It acts as a modulator of µ-, δ-, and κ-opioid receptors.…”

Section: Introductionmentioning

confidence: 99%

<p>Effects of Dexmedetomidine on the Pharmacokinetics of Dezocine, Midazolam and Its Metabolite 1-Hydroxymidazolam in Beagles by UPLC-MS/MS</p>

Zhou¹,

Li²,

Zhao³

et al. 2020

DDDT

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Objective We developed and validated a sensitive and reliable UPLC-MS/MS method for simultaneous determination of dezocine (DEZ), midazolam (MDZ) and its metabolite 1-hydroxymidazolam (1-OH-MDZ) in beagle plasma and investigated the effect of dexmedetomidine (DEX) on the pharmacokinetics of DEZ, MDZ and 1-OH-MDZ in beagles. Materials and Methods Diazepam was used as the internal standard (IS); the three analytes and IS were extracted by acetonitrile precipitation and separated on an Acquity UPLC BEH C18 column using acetonitrile-0.1% formic acid as mobile phase in gradient mode. In positive ion mode, the three analytes and IS were monitored by multiple reaction monitoring (MRM). Six beagles were designed as a double cycle self-control experiment with 0.15 mg/kg in the first cycle (Group A). After a 1-week washout period, the same six beagles were slowly injected intravenously with 2 µg/kg DEX in the second cycle (Group B), with continuous injection for 7 days. On the seventh day, 0.5 hr after intravenous injection of 2 µg/kg DEX, the six beagles were intramuscularly given with DEZ 0.33 mg/kg and MDZ 0.15 mg/kg. Results Under the conditions of this experiment, this method exhibited a good linearity for each analyte. The accuracy and precision were all within the acceptable limits in the bioanalytical method, and the results of recovery, matrix effect and stability have also met the requirements. Conclusion The developed UPLC-MS/MS method for simultaneous determination of DEZ, MDZ and 1-OH-MDZ in beagles plasma was accurate, reproducible, specific, and suitable. DEX could inhibit the metabolism of DEZ and MDZ and increase the exposure of DEZ and MDZ in beagles. Therefore, the change of therapeutic effect and the occurrence of adverse reactions caused by drug–drug interaction should be paid attention to when the drugs were used in combination.

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Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation

Cited by 16 publications

References 40 publications

Dexmedetomidine: What’s New for Pediatrics? A Narrative Review

Dexmedetomidine: What’s New for Pediatrics? A Narrative Review

Effects of Dexmedetomidine on the Pharmacokinetics of Parecoxib and Its Metabolite Valdecoxib in Beagles by UPLC-MS/MS

<p>Effects of Dexmedetomidine on the Pharmacokinetics of Dezocine, Midazolam and Its Metabolite 1-Hydroxymidazolam in Beagles by UPLC-MS/MS</p>

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