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Role of P-Glycoprotein Inhibition for Drug Interactions

Evidence from In Vitro and Pharmacoepidemiological Studies

Abstract

Objectives

We determined in vitro the potency of macrolides as P-glycoprotein inhibitors and tested in hospitalised patients whether coadministration of P-glycoprotein inhibitors leads to increased serum concentrations of the P-glycoprotein substrates digoxin and digitoxin.

Methods

In vitro, the effect of macrolides on polarised P-glycoprotein-mediated digoxin transport was investigated in Caco-2 cells. In a pharmacoepidemiological study, we analysed the serum digoxin and digitoxin concentrations with and without coadministration of P-glycoprotein inhibitors in hospitalised patients.

Results

All macrolides inhibited P-glycoprotein-mediated digoxin transport, with concentrations producing 50% inhibition (IC50) values of 1.8, 4.1, 15.4, 21.8 and 22.7 μmol/L for telithromycin, clarithromycin, roxithromycin, azithromycin and erythromycin, respectively. Coadministration of P-glycoprotein inhibitors was associated with increased serum concentrations of digoxin (1.3 ± 0.6 vs 0.9 ± 0.5 ng/mL, p < 0.01). Moreover, patients receiving macrolides had higher serum concentrations of cardiac glycosides (p < 0.05).

Conclusion

Macrolides are potent inhibitors of P-glycoprotein. Drug interactions between P-glycoprotein inhibitors and substrates are likely to occur during hospitalisation.

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Notes

  1. 1.

    The use of trade names is for product identification purposes only and does not imply endorsement.

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Acknowledgements

Drs Sonja Eberl and Bertold Renner contributed equally to the study. The authors thank Mrs B. Endress for excellent technical assistance and Novartis for providing the PSC-833. This work was supported by grant numbers Fr1298/2–4 and K02120/1–3 from the Deutsche Forschungsgemeinschaft (Bonn, Germany). The authors have no other conflicts of interest that are directly relevant to the content of this study.

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Correspondence to Prof. Martin F. Fromm.

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Eberl, S., Renner, B., Neubert, A. et al. Role of P-Glycoprotein Inhibition for Drug Interactions. Clin Pharmacokinet 46, 1039–1049 (2007). https://doi.org/10.2165/00003088-200746120-00004

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Keywords

  • Digoxin
  • Clarithromycin
  • Macrolides
  • Roxithromycin
  • Cardiac Glycoside