The synthetic opioid fentanyl, after iv administration, is cleared predominantly by hepatic biotransformation (1,2). Fentanyl metabolism is extensive and rapid. Less than 8% administered iv to volunteers was eliminated unchanged, with approximately 6% appearing in urine and 1% excreted in the stool (1), and only 2% was eliminated intact in the urine of surgical patients (3). Metabolites appeared in plasma within 2 min, and plasma metabolite radioactivity exceeded that of parent drug after 30 min (1). More than 80% of the dose was recovered as metabolites, with 76% appearing in the urine and 8% in feces (1). Although these early investigations established the importance of fentanyl biotransformation, the identity of the metabolite(s) was not established.
A few subsequent investigations identified some fentanyl metabolites in humans (fig. 1). The major route of metabolism is N-dealkylation to norfentanyl [4-N-(N-propionylanilino)piperidine] (4), which has been recovered in plasma (5) and urine (4, 6). Considerably less is known, however, about other routes of human fentanyl metabolism. Van Rooy et al. found norfentanyl and despropionylfentanyl [1-(2-phenylethyl)-4-N-anilinopiperidine] in varying amounts in plasma, but no other metabolites were sought (5). In a more thorough evaluation, norfentanyl was identified as the most abundant metabolite and lesser amounts of hydroxynorfentanyl [4-N-(N-hydroxypropionylanilino)piperidine] were found in the urine of all patients (4). Small amounts of hydroxyfentanyl [1-(2-phenylethyl)-4-N-(hydroxypropionylanilino)piperidine] were detected in two of five patients. Hydroxynorfentanyl may be formed either from hydroxyfentanyl or norfentanyl; however, the metabolic origin of hydroxynorfentanyl is unknown. Despropionylfentanyl was not recovered in any patient, in contrast to the report of Van Rooyet al. Unlike fentanyl metabolism in rats (7), no piperidine ring-hydroxylated metabolites were observed in human urine (4). More recently norfentanyl, but not despropionylfentanyl, was found in human urine (6). The fentanyl analogue alfentanil undergoes amide N-dealkylation to N-phenylpropionamide as one of two major routes of metabolism(8 ); however, it is not known whether fentanyl undergoes similar N-dealkylation. Since fentanyl metabolites possesses no significant pharmacological activity (9), the multiple potential routes of fentanyl deactivation and elimination are of substantial therapeutic importance. Nevertheless, there is considerable disagreement and ambiguity regarding human fentanyl metabolism. Therefore, the first objective of this investigation was to identify the routes of human liver microsomal fentanyl metabolism and their relative importance.
