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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

A possible solution to model nonlinearity in elimination and distributional clearances with alpha(2)-adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses

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Author(s):
Gozalo-Marcilla, Miguel [1, 2] ; da Silva, Rodrigo Moreira [3] ; Loureiro Luna, Stelio Pacca [4] ; de Oliveira, Alice Rodrigues [4] ; Fonseca, Mariana Werneck [4] ; Lopes, Norberto Peporine [3] ; Taylor, Polly M. ; Pelligand, Ludovic [5]
Total Authors: 8
Affiliation:
[1] Univ Edinburgh, Royal Dick Sch Vet Studies, Easter Bush Campus, Edinburgh EH25 9RG, Midlothian - Scotland
[2] Univ Edinburgh, Roslin Inst, Easter Bush Campus, Edinburgh EH25 9RG, Midlothian - Scotland
[3] Univ Sao Paulo, NPPNS, Sch Pharmaceut Sci, Ribeirao Preto - Brazil
[4] Sao Paulo State Univ UNESP, Sch Vet Med & Anim Sci, Botucatu, SP - Brazil
[5] Royal Vet Coll, Hatfield, Herts - England
Total Affiliations: 5
Document type: Journal article
Source: JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS; v. 42, n. 6, p. 738-744, NOV 2019.
Web of Science Citations: 0
Abstract

The alpha(alpha)(2)-agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value {[}OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output). (AU)

FAPESP's process: 14/50265-3 - Distribution and metabolism of natural and synthetic xenobiotics: from the comprehension of reactional process to tissue imaging generation
Grantee:Norberto Peporine Lopes
Support Opportunities: BIOTA-FAPESP Program - Thematic Grants
FAPESP's process: 10/08967-0 - Evaluation of clinical and experimental pain in animals
Grantee:Stelio Pacca Loureiro Luna
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 17/01425-6 - Clinical application of different constant rate infusions of detomidine and methadone in standing horses
Grantee:Miguel Gozalo Marcilla
Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
FAPESP's process: 14/00474-5 - Antinociceptive effects and farmacokinetics in horses treated with different low doses of methadone and detomidine
Grantee:Miguel Gozalo Marcilla
Support Opportunities: Scholarships in Brazil - Post-Doctoral