Abstract

Remifentanil is a mu opioid receptor agonist, structurally related to fentanyl, being developed for use in anesthesia. Remifentanil was designed to be cleared rapidly by ester hydrolysis. To determine the pharmacokinetics of remifentanil in conscious beagle dogs, venous blood was collected at various times during and after the end of a 25 min intravenous infusion of the compound (0.36 or 36.0 micrograms [free base]/kg/min). In a separate set of studies designed to measure tissue clearance of remifentanil, catheters were implanted in various blood vessels of anesthetized beagle dogs to sample blood entering and leaving selected tissues. Approximately 40 min (steady state achieved) after initiation of remifentanil infusions at the same rates as described above, and while infusions were still in progress, blood was collected from the series of catheters. In a third set of experiments, blood obtained from either untreated dogs or from a dog that had been anesthetized, was incubated with remifentanil (either 10 or 1000 ng (free base)/ml). The observed half-life was used to provide an estimate of in vivo blood metabolic clearance of the compound. Extracts of the blood from all experiments were analyzed by either an HPLC or mass spectrometry assay for remifentanil concentration. There were no differences in systemic clearance (approximately 45 ml/kg/min), volume of distribution at steady state, mean residence time, dose-normalized normalized concentration at steady state, or dose-normalized AUC between the doses administered to conscious dogs; the t1/2 alpha was 3-5 min. In the anesthetized animals, muscle and intestine had the highest tissue clearance rates, but liver, kidneys, and blood each accounted for 1% or less of systemic clearance. The results indicate that, within the range of doses studied, the pharmacokinetics of remifentanil during infusion to steady state in dogs were not dependent on dose, and that the liver contributed very minimally to the overall clearance of the compound.