P-glycoprotein-mediated intestinal and biliary digoxin transport in humans

  • Drescher S
  • Glaeser H
  • Mürdter T
 et al. 
  • 27

    Readers

    Mendeley users who have this article in their library.
  • 136

    Citations

    Citations of this article.

Abstract

Background and aims: Intestinal transport by P-glycoprotein is a recently recognized determinant of drug disposition. However, direct measurements of transporter-mediated drug elimination into isolated segments of human small intestine are lacking. Methods: Using a recently developed intestinal perfusion catheter, we perfused in healthy volunteers two 20-cm jejunal segments with and without the P-glycoprotein inhibitor quinidine before and during administration of the P-glycoprotein inducer rifampin (INN, rifampicin). Results: Within 3 hours after intravenous administration of digoxin (1 mg), perfusate samples were collected. We found that 0.45% ± 0.24% and 0.83% ± 0.60% of the digoxin dose were eliminated into a jejunal segment and into bile, respectively. Perfusion of the isolated segment with quinidine reduced intestinal digoxin elimination (0.23% ± 0.08%, P = .031). During rifampin, intestinal digoxin elimination was 0.80 ± 0.59 (P = .383). Enterocyte P-glycoprotein content correlated with the area under the plasma concentration-time curve of digoxin (Spearman nonparametric correlation coefficient [rs] = -0.73, P = .003) and digoxin nonrenal clearance (rs= 0.52, P = .056), as well as with intraluminal and plasma concentrations of quinidine (rs= 0.55, P = .041 and rs= -0.67, P = .009, respectively). Conclusion: Using segmental intestinal perfusion, we provide direct evidence that intestinal P-glycoprotein mediates substantial drug elimination after intravenous administration from the systemic circulation into the gut lumen and prevents entry of luminally administered P-glycoprotein substrates into the enterocytes. These data also highlight the relative importance of direct intestinal drug secretion in comparison with drug elimination through bile.

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document

Authors

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free