Pharmacokinetics of midazolam in sevoflurane-anesthetized cats.

OBJECTIVE

To estimate the pharmacokinetics of midazolam and 1-hydroxymidazolam after midazolam administration as an intravenous bolus in sevoflurane-anesthetized cats.

STUDY DESIGN

Prospective pharmacokinetic study.

ANIMALS

A group of six healthy adult, female domestic cats.

METHODS

Anesthesia was induced and maintained with sevoflurane. After 30 minutes of anesthetic equilibration, cats were administered midazolam (0.3 mg kg) 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 (f), rectal temperature, noninvasive mean arterial pressure (MAP) and end-tidal carbon dioxide (Pe'CO) 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.

RESULTS

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, 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 kg, respectively. No significant changes in HR, MAP, f or Pe'CO were observed following midazolam administration.

CONCLUSION AND CLINICAL RELEVANCE

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.