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High-dose naloxone, an experimental tool uncovering latent sensitisation: pharmacokinetics in humans
- Source :
- British Journal of Anaesthesia. 123:e204-e214
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Background Naloxone, an opioid receptor antagonist, is used as a pharmacological tool to detect tonic endogenous activation of opioid receptors in experimental pain models. We describe a pharmacokinetic model linking naloxone pharmacokinetics to its main metabolite after high-dose naloxone infusion. Methods Eight healthy volunteers received a three-stage stepwise high-dose i.v. naloxone infusion (total dose 3.25 mg kg−1). Naloxone and naloxone-3-glucuronide (N3G) plasma concentrations were sampled from infusion onset to 334 min after infusion discontinuation. Pharmacokinetic analysis was performed using non-linear mixed effect models (NONMEM). The predictive performances of Dowling's and Yassen's models were evaluated, and target-controlled infusion simulations were performed. Results Three- and two-compartment disposition models with linear elimination kinetics described the naloxone and N3G concentration time-courses, respectively. Two covariate models were developed: simple (weight proportional) and complex (with the shallow peripheral volume of distribution linearly increasing with body weight). The median prediction error (MDPE) and wobble for Dowling's model were –32.5% and 33.4%, respectively. For Yassen's model, the MDPE and wobble were 1.2% and 19.9%, respectively. Conclusions A parent–metabolite pharmacokinetic model was developed for naloxone and N3G after high-dose naloxone infusion. No saturable pharmacokinetics were observed. Whereas Dowling's model was inaccurate and over-predicted naloxone concentrations, Yassen's model accurately predicted naloxone pharmacokinetics. The newly developed covariate models may be used for high-dose TCI-naloxone for experimental and clinical practice. Clinical trials registration NCT01992146.
- Subjects :
- Adult
Male
Volume of distribution
Adolescent
Naloxone
medicine.drug_class
business.industry
Narcotic Antagonists
Metabolite
Antagonist
Pharmacology
NONMEM
Young Adult
chemistry.chemical_compound
Anesthesiology and Pain Medicine
Pharmacokinetics
chemistry
Opioid
Opioid receptor
medicine
Humans
business
Endogenous opioid
medicine.drug
Subjects
Details
- ISSN :
- 00070912
- Volume :
- 123
- Database :
- OpenAIRE
- Journal :
- British Journal of Anaesthesia
- Accession number :
- edsair.doi.dedup.....6a1700deea92d0caf9fd36e13b67271d
- Full Text :
- https://doi.org/10.1016/j.bja.2018.12.007