Akihiro Ando1, Shinichiro Sasago2, Yoshihiro Ohzone3, Yohei Miyamoto4. 1. 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. 2. Department of Bio Research, Kamakura Techno-Science, Inc., 6-10-1, Tebiro, Kamakura, Kanagawa, 248-0036, Japan. 3. ADME & Tox. Research Institute, Sekisui Medical Co., Ltd., 2117 Muramatsu, Tokai-mura, Naka-gun, Ibaraki, 319-1182, Japan. 4. Pharmaceutical Clinical Research Department, Toray Industries, Inc., 1-1, Nihonbashi-muromachi 2-chome, Chuo-ku, Tokyo, 103-8666, Japan.
Abstract
BACKGROUND AND 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.
BACKGROUND AND OBJECTIVE:Nalfurafine hydrochloride (TRK-820), which exhibits strong κ-opioid agonistic activity, has an antipruritic effect on uremic pruritus. The permeability of nalfurafine across humanP-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: H Nagase; J Hayakawa; K Kawamura; K Kawai; Y Takezawa; H Matsuura; C Tajima; T Endo Journal: Chem Pharm Bull (Tokyo) Date: 1998-02 Impact factor: 1.645