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Characterisation of (R/S)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein

Naunyn-Schmiedeberg's Archives of Pharmacology volume 371, pages 195–201 (2005)Cite this article

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 and N-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 and N-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 and N-desalkylpropafenone inhibited P-glycoprotein-mediated digoxin transport with IC50 values of 6.8, 19.9, and 21.3 μM, respectively. In summary, whereas propafenone and N-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 and N-desalkylpropafenone are inhibitors of human P-glycoprotein and therefore contribute to the digoxin–propafenone interaction observed in humans.

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Acknowledgements

We are grateful to Mrs. Monika Seiler for expert technical assistance. This work was supported by the Robert Bosch Foundation (Stuttgart, Germany) and the Deutsche Forschungsgemeinschaft (Fr 1298/2-3, Bonn, Germany).

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Affiliations

  1. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstrasse 17, 91054, Erlangen, Germany

    Iouri Bachmakov & Martin F. Fromm

  2. Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376, Stuttgart, Germany

    Sabine Rekersbrink, Ute Hofmann, Michel Eichelbaum & Martin F. Fromm

Authors
  1. Iouri Bachmakov
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  2. Sabine Rekersbrink
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  3. Ute Hofmann
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  4. Michel Eichelbaum
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  5. Martin F. Fromm
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Correspondence to Martin F. Fromm.

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Bachmakov, I., Rekersbrink, S., Hofmann, U. et al. Characterisation of (R/S)-propafenone and its metabolites as substrates and inhibitors of P-glycoprotein. Naunyn-Schmiedeberg's Arch Pharmacol 371, 195–201 (2005). https://doi.org/10.1007/s00210-005-1025-y

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  • DOI: https://doi.org/10.1007/s00210-005-1025-y

Keywords

  • (R/S)-Propafenone
  • 5-Hydroxypropafenone
  • N-desalkylpropafenone
  • P-glycoprotein
  • Caco-2
  • Drug transport
  • Drug interaction