Pharmacokinetic and pharmacodynamic analysis comparing diverse effects of detomidine,medetomidine, and dexmedetomidine in the horse: a population analysis |
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| Authors: | K N Grimsrud S Ait‐Oudhia B P Durbin‐Johnson D M Rocke K R Mama M L Rezende S D Stanley W J Jusko |
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| Institution: | 1. Campus Veterinary Services, School of Veterinary Medicine, University of California, Davis, CA, USA;2. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, Buffalo, NY, USA;3. Department of Public Health Sciences, School of Medicine, University of California Davis, Sacramento, CA, USA;4. Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA;5. K.L. Maddy Equine Analytical Chemistry Laboratory, California Animal Health and Food Safety Laboratory, School of Veterinary Medicine, University of California, Davis, CA, USA |
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| Abstract: | The present study characterizes the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the α2‐adrenergic receptor agonists detomidine (DET), medetomidine (MED) and dexmedetomidine (DEX) in parallel groups of horses from in vivo data after single bolus doses. Head height (HH), heart rate (HR), and blood glucose concentrations were measured over 6 h. Compartmental PK and minimal physiologically based PK (mPBPK) models were applied and incorporated into basic and extended indirect response models (IRM). Population PK/PD analysis was conducted using the Monolix software implementing the stochastic approximation expectation maximization algorithm. Marked reductions in HH and HR were found. The drug concentrations required to obtain inhibition at half‐maximal effect (IC50) were approximately four times larger for DET than MED and DEX for both HH and HR. These effects were not gender dependent. Medetomidine had a greater influence on the increase in glucose concentration than DEX. The developed models demonstrate the use of mechanistic and mPBPK/PD models for the analysis of clinically obtainable in vivo data. |
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