BIOTRANSFORMATION OF FENTANYL .2. ACUTE DRUG-INTERACTIONS IN RATS AND MEN

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  • 1 January 1982
    • journal article
    • research article
    • Vol. 31  (5) , 221-227
Abstract
Rat tissue homogenates were used to study fentanyl biotransformation. The liver was shown to be the most important metabolizing organ, whereas extrahepatic metabolism occurred only to a minor degree in the kidneys. The products of oxidative desalkylation, phenylacetic acid and norfentanyl, could be identified as well as small amounts of p-hydroxy(phenethyl)fentanyl, which is pharmacologically still active. Major sex differences were observed, male rats showing nearly twice as much activity as female animals. Several anesthetic agents, often used in combination with fentanyl, were tested with respect to their influence on fentanyl metabolism. Most of them caused an inhibition of biotransformation and/or variations in product distribution, when they were added to in vitro incubations or given to the animals prior to enzyme preparation. This experimental design proved to be useful as a screening method to predict metabolic drug interactions. Halothane and enflurane, which are strong inhibitors in rats, were demonstrated to delay fentanyl metabolism in man. Fentanyl plasma levels under halothane anesthesia were more than twice as high as during neuroleptanesthesia. The importance of other agents, ketamine, promethazine or local anesthetics, remains to be examined. Variations of biotransformation reactions among patients as well as the reported drug interactions might explain some differences in fentanyl blood concentrations but must also be taken into account when intensity and duration of effects or side effects are discussed.