Nalfurafine hydrochloride (TRK-820) exhibits strong к-opioid agonistic activity and is a new antipruritic agent for uremic pruritus. This study was performed to identify the human hepatic cytochrome P450 isoforms involved in the metabolic conversion of nalfurafine to the decyclopropylmethylated form, de-CPM, using human liver microsomes and E. coli membrane fractions expressing human P450 isoforms. Samples were analysed by liquid chromatography with a radioactivity detector and liquid chromatography-tandem mass spectrometry. The metabolism of nalfurafine by human liver microsomes exhibited a biphasic kinetic profile. Experiments examining the metabolism by E. coli membrane fractions expressing human P450 isoforms indicated that CYP1A1, 2C8, 2C19 and 3A4 had the ability to produce de-CPM. In experiments with human liver microsomes that examined the inhibition of nalfurafine metabolism by anti-human P450 antibodies, anti-CYP3A4 antibody predominantly, and anti-CYP2C8 and 2C19 antibodies moderately, inhibited de-CPM formation. From these results, CYP3A4 appeared to be the major isoform involved in the metabolic decyclopropylmethylation of nalfurafine, while CYP2C8 and 2C19 most likely play a minor role in the formation of de-CPM.
Copyright © 2012 John Wiley & Sons, Ltd.