title: Drug-Drug Interactions of a Novel κ-Opioid Receptor Agonist, Nalfurafine Hydrochloride, Involving the P-Glycoprotein.
abstract: OBJECTIVE
  Nalfurafine hydrochloride (TRK-820), which exhibits strong κ-opioid agonistic activity, has an antipruritic effect on uremic pruritus. The permeability of nalfurafine across human P-glycoprotein (P-gp)-expressing LLC-PK1 cells was investigated to evaluate drug-drug interactions (DDI) involving the P-gp efflux transporter of nalfurafine. Furthermore, we assessed the ratio of brain/plasma concentrations (K p) as an indicator to investigate the changes in the blood-brain barrier (BBB) transport through P-gp when digoxin or verapamil was concomitantly administered with nalfurafine in mice.
  
  
  METHODS
  All samples were analyzed by liquid chromatography-tandem mass spectrometry or a liquid scintillation counter.
  
  
  RESULTS
  The cleared volume ratio (cleared volume from basal to apical/cleared volume from apical to basal) of nalfurafine in P-gp-expressing cells was higher than that in the control cells; however, no concentration-dependent decrease in the cleared volume ratio of digoxin was observed in the presence of nalfurafine. The K p value in mice showed similar profiles to those observed with nalfurafine alone and when co-administered with digoxin or verapamil.
  
  
  CONCLUSIONS
  From these results, nalfurafine was found to be a substrate for P-gp, but had no inhibitory effect on P-gp-mediated transport. Furthermore, it is unlikely that nalfurafine transport via the BBB is affected by P-gp substrates in humans.
authors.affiliation: Pharmaceutical Clinical Research Department, Toray Industries, Inc., 1-1, Nihonbashi-muromachi 2-chome, Chuo-ku, Tokyo, 103-8666, Japan. Akihiro_Ando@nts.toray.co.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ando
authors.affiliation: Department of Bio Research, Kamakura Techno-Science, Inc., 6-10-1, Tebiro, Kamakura, Kanagawa, 248-0036, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Sasago
authors.affiliation: ADME & Tox. Research Institute, Sekisui Medical Co., Ltd., 2117 Muramatsu, Tokai-mura, Naka-gun, Ibaraki, 319-1182, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ohzone
authors.affiliation: Pharmaceutical Clinical Research Department, Toray Industries, Inc., 1-1, Nihonbashi-muromachi 2-chome, Chuo-ku, Tokyo, 103-8666, Japan.
authors.forename: Yohei
authors.initials: Y
authors.lastname: Miyamoto
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004077:Digoxin / Q000008:administration & dosage; D004347:Drug Interactions; D006801:Humans; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009019:Morphinans / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism*; D010539:Permeability; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013141:Spiro Compounds / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism*; D013552:Swine; D014700:Verapamil / Q000008:administration & dosage
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D009019:Morphinans; D017473:Receptors, Opioid, kappa; D013141:Spiro Compounds; C111212:TRK 820; D004077:Digoxin; D014700:Verapamil