[Biotransformation of fentanyl. III. Effect of chronic drug exposure on the distribution, metabolism and excretion in the rat]

Abstract

In male Wistar rats, tissue distribution and excretion of fentanyl and its metabolites were studied after intravenous of intramuscular injection. Oxidative desalkylation leading to phenylacetic acid and norfentanyl proved to be the main degradation pathway in-vivo, whereas other metabolites, including the pharmacologically still active p-hydroxy(phenethyl)fentanyl were formed only in minor quantities. All compounds could be detected in any tissue under study (brain, lung, liver, kidney, muscle and fat) as well as in the gastric contents, the amount of fentanyl in the latter cumulating to about 2% of the total dose 60 min after injection, compared with about 10% in the fat. In rats chronically treated with ethanol, nicotine, morphine, phenobarbital, promethazine or diazepam, major differences in in-vitro fentanyl metabolism by liver homogenates were observed including both inhibition and induction. Phenobarbital pretreatment also induced extrahepatic biotransformation in kidney, adrenals and intestinal mucosa. On the other hand, tissue concentrations of fentanyl and its metabolites did not clearly reflect the in-vitro changes in metabolic activity. Fentanyl brain levels were found to be lower in the treatment groups but seemed not to correlate with pharmacodynamics, less effects following injection being observed only after ethanol and morphine. The in-vitro metabolic drug interaction proved to be of less importance than changes in diuresis and/or urinary pH when excretion products were analysed. As a conclusion, it is suggested that altered sensitivity of brain tissue rather than changes in bioavailability must explain variations in dose-response relationship which are frequently believed to be seen when fentanyl is used in patients with chronic drug administration.