Pharmacokinetics of midazolam in sevoflurane-anesthetized cats.

Urshulaa Dholakia, Reza Seddighi, Sherry K Cox, Xiaocun Sun, Bruno H Pypendop

Veterinary anaesthesia and analgesia 2020 Mar

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To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats. Prospective pharmacokinetic study. A group of six healthy adult, female domestic cats. Anesthesia was induced and maintained with sevoflurane. After 30 minutes of anesthetic equilibration, cats were administered midazolam (0.3 mg kg-1) over 15 seconds. Venous blood was collected at 0, 1, 2, 4, 8, 15, 30, 45, 90, 180 and 360 minutes after administration. Plasma concentrations for midazolam and 1-hydroxymidazolam were measured using high-pressure liquid chromatography. The heart rate (HR), respiratory rate (fR), rectal temperature, noninvasive mean arterial pressure (MAP) and end-tidal carbon dioxide (Pe'CO2) were recorded at 5 minute intervals. Population compartment models were fitted to the time-plasma midazolam and 1-hydroxymidazolam concentrations using nonlinear mixed effect modeling. The pharmacokinetic model was fitted to the data from five cats, as 1-hydroxymidazolam was not detected in one cat. A five-compartment model best fitted the data. Typical values (% interindividual variability where estimated) for the volumes of distribution for midazolam (three compartments) and hydroxymidazolam (two compartments) were 117 (14), 286 (10), 705 (14), 53 (36) and 334 mL kg-1, respectively. Midazolam clearance to 1-hydroxymidazolam, midazolam fast and slow intercompartmental clearances, 1-hydroxymidazolam clearance and 1-hydroxymidazolam intercompartment clearance were 18.3, 63.5 (15), 22.1 (8), 1.7 (67) and 3.8 mL minute-1 kg-1, respectively. No significant changes in HR, MAP, fR or Pe'CO2 were observed following midazolam administration. In sevoflurane-anesthetized cats, a five-compartment model best fitted the midazolam pharamacokinetic profile. There was a high interindividual variability in the plasma 1-hydroxymidazolam concentrations, and this metabolite had a low clearance and persisted in the plasma for longer than the parent drug. Midazolam administration did not result in clinically significant changes in physiologic variables. Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.

Citation

Urshulaa Dholakia, Reza Seddighi, Sherry K Cox, Xiaocun Sun, Bruno H Pypendop. Pharmacokinetics of midazolam in sevoflurane-anesthetized cats. Veterinary anaesthesia and analgesia. 2020 Mar;47(2):200-209