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Increased Absorption of Digoxin from the Human Jejunum Due to Inhibition of Intestinal Transporter-Mediated Efflux

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Abstract

Background and objectives

The contribution of transport in the small intestine by the apically located efflux pump P-glycoprotein to variable drug absorption in humans is still poorly understood. We therefore investigated whether inhibition of intestinal P-glycoprotein-mediated efflux by quinidine leads to increased absorption of the P-glycoprotein substrate digoxin.

Methods

Using a multilumen perfusion catheter, we investigated the impact of P-glycoprotein inhibition on absorption of two compounds: the P-glycoprotein substrate digoxin and the marker for passive transcellular absorption antipyrine. Two 20cm adjacent jejunal segments were isolated with the multilumen perfusion catheter in seven healthy subjects. Unlabelled and deuterated digoxin and antipyrine, respectively, were simultaneously infused into either of the intestinal segments. One of the segments was additionally perfused with the P-glycoprotein inhibitor quinidine. Intestinal perfusates were collected for 3 hours, and drug concentrations were determined in the intestinal perfusates, plasma and urine.

Results

Quinidine did not affect the disposition of antipyrine. In contrast, coadministration of quinidine into one jejunal segment caused a considerable increase in the amount of digoxin absorbed from this segment compared with the absorption from the other quinidine-free segment (22.3 ± 8.9% vs 55.8 ± 21.2% of the dose; p < 0.05). Accordingly, the area under the plasma concentration-time curve and the maximum plasma concentration of digoxin were considerably higher when luminal quinidine was coadministered (p < 0.05 and p < 0.001, respectively). Differences in digoxin absorption from the two intestinal segments were also reflected by pronounced differences in urinary digoxin elimination (5.5 ± 3.3% vs 19.2 ± 8.1% of the dose; p < 0.01).

Conclusions

P-glycoprotein inhibition in enterocytes increases systemic exposure of orally administered drugs that are P-glycoprotein substrates. These data highlight the importance of the small intestine as an active barrier against xenobiotics.

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Notes

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

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Acknowledgements

The authors thank Mrs Anja Bengel, Mrs Silvia Kubitzsch, Mrs Sabine Rekersbrink and Mr Frank Schönberger for excellent technical assistance.

This work was supported by the Robert Bosch Foundation (Stuttgart, Germany), a grant from the Bundesministerium für Bildung und Forschung (BMBF grant BEO 0311782), the Deutsche Forschungsgemeinschaft (Bonn, Germany; Fr1298/2-4) and the University of Adelaide Research Scheme (Adelaide, South Australia, Australia). All authors were independent in conducting the study and preparing the manuscript. The authors have no conflicts of interest that are directly relevant to the content of this study.

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Authors and Affiliations

  1. Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, and University of Tübingen, Tübingen, Germany

    Svitlana Igel, Siegfried Drescher, Thomas Mürdter, Ute Hofmann, Georg Heinkele, Heike Tegude, Hartmut Glaeser, Stefanie S. Brenner, Michel Eichelbaum & Martin F. Fromm (MD)

  2. Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-University Erlangen-Nuremberg, Fahrstr. 17, 91054, Erlangen, Germany

    Siegfried Drescher, Heike Tegude, Hartmut Glaeser & Martin F. Fromm (MD)

  3. Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, South Australia, Australia

    Andrew A. Somogyi

  4. Centre for Pediatric & Adolescent Gastroenterology, Women’s & Children’s Hospital, North Adelaide, South Australia, Australia

    Taher Omari

  5. Department of Internal Medicine I, Robert Bosch Hospital, Stuttgart, Germany

    Christian Schäfer

Authors
  1. Svitlana Igel
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  2. Siegfried Drescher
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  4. Ute Hofmann
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  9. Andrew A. Somogyi
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  11. Christian Schäfer
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  12. Michel Eichelbaum
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  13. Martin F. Fromm
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Corresponding author

Correspondence to Martin F. Fromm.

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Igel, S., Drescher, S., Mürdter, T. et al. Increased Absorption of Digoxin from the Human Jejunum Due to Inhibition of Intestinal Transporter-Mediated Efflux. Clin Pharmacokinet 46, 777–785 (2007). https://doi.org/10.2165/00003088-200746090-00005

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  • DOI: https://doi.org/10.2165/00003088-200746090-00005

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