Drug-Drug Interactions of a Novel κ-Opioid Receptor Agonist, Nalfurafine Hydrochloride, Involving the P-Glycoprotein.

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.

• Authors: Akihiro Ando, Shinichiro Sasago, Yoshihiro Ohzone, Yohei Miyamoto
• Journal: European journal of drug metabolism and pharmacokinetics (Eur J Drug Metab Pharmacokinet) Vol. 41 Issue 5 Pg. 549-58 (Oct 2016) ISSN: 2107-0180 [Electronic] France
• PMID: 26058994 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B
• Morphinans
• Receptors, Opioid, kappa
• Spiro Compounds
• TRK 820
• Digoxin
• Verapamil

Topics

• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• Animals
• Biological Transport (drug effects)
• Blood-Brain Barrier (metabolism)
• Brain (metabolism)
• Cell Line
• Digoxin (administration & dosage)
• Drug Interactions
• Humans
• LLC-PK1 Cells
• Male
• Mice
• Mice, Inbred ICR
• Morphinans (administration & dosage, blood, metabolism)
• Permeability
• Receptors, Opioid, kappa (agonists)
• Spiro Compounds (administration & dosage, blood, metabolism)
• Swine
• Verapamil (administration & dosage)