Identification of human cytochrome P450 enzymes involved in the metabolism of a novel к-opioid receptor agonist, nalfurafine hydrochloride.

Abstract

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.

• Authors: Akihiro Ando, Keiyu Oshida, Shinichi Fukuyama, Ayano Watanabe, Hisashi Hashimoto, Yohei Miyamoto
• Journal: Biopharmaceutics & drug disposition (Biopharm Drug Dispos) Vol. 33 Issue 5 Pg. 257-64 (Jul 2012) ISSN: 1099-081X [Electronic] England
• PMID: 22581509 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 John Wiley & Sons, Ltd.

Chemical References

• Cytochrome P-450 Enzyme Inhibitors
• Morphinans
• Receptors, Opioid, kappa
• Spiro Compounds
• TRK 820
• Cytochrome P-450 Enzyme System
• Aryl Hydrocarbon Hydroxylases
• CYP1A1 protein, human
• CYP2C19 protein, human
• CYP2C8 protein, human
• Cytochrome P-450 CYP1A1
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP2C8
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human

Topics

• Aryl Hydrocarbon Hydroxylases (genetics, metabolism)
• Biotransformation
• Cell Membrane (enzymology, genetics)
• Cytochrome P-450 CYP1A1 (genetics, metabolism)
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP2C8
• Cytochrome P-450 CYP3A (genetics, metabolism)
• Cytochrome P-450 Enzyme Inhibitors
• Cytochrome P-450 Enzyme System (genetics, metabolism)
• Escherichia coli (enzymology, genetics)
• Humans
• In Vitro Techniques
• Methylation
• Microsomes, Liver (drug effects, enzymology)
• Molecular Structure
• Morphinans (metabolism, pharmacokinetics)
• Receptors, Opioid, kappa (agonists)
• Spiro Compounds (metabolism, pharmacokinetics)