Pharmacokinetics of 3H-Fentanyl in the Dog Anesthetized with Enflurane

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Abstract
Fentanyl is often used as an anesthetic supplement for short procedures because it has a rapid onset and brief duration of action. However, persistence of ventilatory depression several hours following the last dose has been seen. The pharmacokinetics of fentanyl in the dog were studied to find an explanation for the occasionally prolonged duration of action. 3H-fentanyl citrate, 10 or 100 .mu.g/kg, was injected i.v. in dogs anesthetized with enflurane-O2. Arterial plasma and urine were analyzed for unchanged 3H-fentanyl and for total 3H radioactivity. Kinetic indices were derived by nonlinear least-squares analysis of log concentration (ng/ml) vs. time relationships. Initially, the elimination of fentanyl from plasma was very rapid, and 98% of the amount administered was removed from plasma in the 1st 5 min after an i.v. injection. The terminal elimination phase was prolonged (t1/2 [half-life] = 199 .+-. 17 min). The apparent volume of distribution was large (9.8 l/kg) and independent of dose. Repetitive doses produced an accumulation of fentanyl. 3H-labeled metabolites of fentanyl were present in the earliest samples of plasma, and accounted for the major portion of the total 3H radioactivity in both plasma and urine. Urine collected for 6 h contained 36% of the total 3H radioactivity administered, but only 4% of fentanyl administered was excreted as unchanged fentanyl. Apparently most of a single dose of fentanyl is rapidly eliminated from plasma (and presumably brain) by biotransformation to inactive metabolites and by uptake of the active drug by body tissues. The high affinity of tissues for fentanyl limits the rate of its ultimate elimination from the body by biotransformation and leads to accumulation of the drug when administered in very large or repeated doses. Under these circumstances the slow release of drug from tissues results in persistent plasma levels of fentanyl and a prolonged duration of action.

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