Dose-independent Pharmacokinetics of Fentanyl

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Abstract
Fentanyl is used as an analgesic in small doses (1-2 .mu.g/kg) and as an anesthetic in very large doses (> 150 .mu.g/kg). The effects of fentanyl correlate with its concentrations in plasma. It is important to know whether or not the pharmacokinetics of fentanyl vary with dose size to predict the plasma concentrations and effects produced by various dosage regimens. The pharmacokinetics of fentanyl was studied in dogs. 3H-fentanyl (2.5-640 .mu.g/kg) was injected i.v. 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/ml) vs. time after a bolus injection. The terminal elimination half-time (t1/2.beta. = 211 min), the apparent volume of distribution (9.5 l/kg), the volume of the central compartment (1.14 l/kg) and the clearance (37 ml/kg per min) of fentanyl were independent of dose over the 6.4-640 .mu.g/kg dose range. The distribution volume and distribution half-times were lower for the 2.5 .mu.g/kg than for some of the larger doses; this was attributed to differences in experimental conditions. Apparently, the pharmacokinetics of fentanyl are dose independent, certainly over the 6.4-640 .mu.g/kg dose range. There is no evidence of saturation of biotransformation or tissue uptake mechanisms for doses in the range of 2.5 to 640 .mu.g/kg.