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- Title
Characterisation of (R/S)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein.
- Authors
Bachmakov, Iouri; Rekersbrink, Sabine; Hofmann, Ute; Eichelbaum, Michel; Fromm, Martin F.
- Abstract
Digoxin is a drug with a narrow therapeutic index, which is a substrate of the ATP-dependent efflux pump P-glycoprotein. Increased or decreased digoxin plasma concentrations occur in humans due to the inhibition or induction of this drug transporter in organs with excretory function such as small intestine, liver and kidney. It is well known that serum concentrations of digoxin increase considerably in humans if propafenone is given simultaneously. However, it has not been investigated in detail whether propafenone and its metabolites are substrates and/or inhibitors of human P-glycoprotein. The aim of this study, therefore, was to investigate the P-glycoprotein-mediated transport and inhibition properties of propafenone and its major metabolites 5-hydroxypropafenone andN-desalkylpropafenone in Caco-2 cell monolayers. Inhibition of P-glycoprotein-mediated transport by propafenone and its metabolites was determined using digoxin as a P-glycoprotein substrate. No polarised transport was observed for propafenone andN-desalkylpropafenone in Caco-2 cell monolayers. However, 5-hydroxypropafenone translocation was significantly greater from basal-to-apical compared with apical-to-basal (Papp basal-apical vs.Papp apical-basal, 10.21±2.63×10-6 vs. 4.34±1.84×10-6 cm/s;P<0.01). Moreover, propafenone, 5-hydroxypropafenone andN-desalkylpropafenone inhibited P-glycoprotein-mediated digoxin transport with IC50 values of 6.8, 19.9, and 21.3 µM, respectively. In summary, whereas propafenone andN-desalkylpropafenone are not substrates of P-glycoprotein, 5-hydroxypropafenone is translocated by human P-glycoprotein across cell monolayers. In addition, propafenone and its two major metabolites 5-hydroxypropafenone andN-desalkylpropafenone are inhibitors of human P-glycoprotein and therefore contribute to the digoxin-propafenone interaction observed in humans.
- Subjects
GLYCOPROTEINS; DIGOXIN; CARDENOLIDES; CARDIAC glycosides; METABOLITES; GLYCOCONJUGATES
- Publication
Naunyn-Schmiedeberg's Archives of Pharmacology, 2005, Vol 371, Issue 3, p195
- ISSN
0028-1298
- Publication type
Article
- DOI
10.1007/s00210-005-1025-y