Dose-Independent Pharmacokinetics of Fentanyl

Abstract

Fentanyl is used as an analgesic in small doses (1-2 micrograms X kg-1) and as an anesthetic in very large doses (greater than 150 micrograms X kg-1). It has been demonstrated that the effects of fentanyl correlate with its concentrations in plasma. It is important, therefore, to know whether or not the pharmacokinetics of fentanyl vary with dose size in order to predict the plasma concentrations and effects produced by various dosage regiments. The authors studied the pharmacokinetics of fentanyl in dogs. 3H-fentanyl (2.5-640 micrograms X kg-1) was injected intravenously in dogs anesthetized at a stable level with enflurane-O2. Arterial plasma and urine were analyzed for unchanged 3H-fentanyl. Kinetic indices were derived by nonlinear least-squares analysis of log concentration of fentanyl in plasma (ng X ml-1) versus time after a bolus injection. The terminal elimination half-time (t 1/2 beta = 211 min), the apparent volume of distribution (9.5 l X kg-1), the volume of the central compartment (1.14 l X kg-1), and the clearance (37 ml X kg-1 X min-1) of fentanyl were independent of dose over the 6.4-640 micrograms X kg-1 dose range. The distribution volume and distribution half-times were lower for the 2.5 micrograms X kg-1 than for some of the larger doses; this was attributed to differences in experimental conditions. The authors conclude that the pharmacokinetics of fentanyl are dose independent certainly over the 6.4-640 micrograms X kg-1 dose range. There is no evidence of saturation of biotransformation or tissue uptake mechanisms for doses in the range of 2.5 to 640 micrograms X kg-1.