title: In vitro and in vivo pharmacological characterization of the main metabolites of nalfurafine hydrochloride.
abstract: Pharmacological characterization of the main metabolites of nalfurafine hydrochloride ((E)-N-[17-(cyclopropylmethyl)-4,5α-epoxy-3,14-dihydroxymorphinan-6β-yl]-3-(furan-3-yl)-N-methylprop-2-enamide monohydrochloride; a selective κ-opioid receptor agonist and an antipruritic for uremic pruritus in hemodialysis patients in Japan) such as 17-decyclopropylmethylated nalfurafine (de-CPM), 3-glucuronide of nalfurafine (NFA-G) and 3-glucuronide of 17-decyclopropylmethylated nalfurafine (de-CPM-G) was performed in vitro (human opioid receptor radioligand binding assay and forskolin-stimulated cyclic adenosine monophosphate (cAMP) assay) and in vivo (substance P-induced scratching behavior in mice). These main metabolites of nalfurafine showed the low affinities for human κ-, μ- and δ-opioid receptors except for the affinity of de-CPM to κ-opioid receptor (inhibition constant (Ki) values: 5.95nmol/l), which was 24 times lower than that of nalfurafine. Moreover, the main metabolites of nalfurafine had much lower agonistic activities than that of nalfurafine for three opioid receptors in forskolin-stimulated cAMP assays. In the substance P-induced mouse scratching behavior, the subcutaneous administration of each metabolite did not statistically significantly reduce the scratching behavior at doses up to 1000μg/kg which was 100 times higher than the effective dose of nalfurafine. These findings suggest that the main metabolites of nalfurafine do not make any contribution to its pharmacological actions including antipruritic effects in vivo.
authors.affiliation: Pharmaceutical Research Laboratories, Toray Industries, Inc., 10-1 Tebiro 6-chome, Kamakura, Kanagawa, Japan. Kaoru_Nakao@nts.toray.co.jp
authors.forename: Kaoru
authors.initials: K
authors.lastname: Nakao
authors.forename: Yuko
authors.initials: Y
authors.lastname: Togashi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Honda
authors.forename: Shinobu
authors.initials: S
authors.lastname: Momen
authors.forename: Hideo
authors.initials: H
authors.lastname: Umeuchi
authors.forename: Shinji
authors.initials: S
authors.lastname: Sakakibara
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Okano
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mochizuki
mesh_terms: D000818:Animals; D000982:Antipruritics / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009019:Morphinans / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D011537:Pruritus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D013141:Spiro Compounds / Q000378:metabolism* / Q000494:pharmacology* / Q000627:therapeutic use; D013373:Substance P / Q000009:adverse effects
chemical_list: D000982:Antipruritics; D009019:Morphinans; D011957:Receptors, Opioid; D013141:Spiro Compounds; C111212:TRK 820; D013373:Substance P