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

Clin Pharmacol Ther. 2003 Mar;73(3):223-31. doi: 10.1067/mcp.2003.27.


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 [r(S)] = -0.73, P =.003) and digoxin nonrenal clearance (r(S) = 0.52, P =.056), as well as with intraluminal and plasma concentrations of quinidine (r(S) = 0.55, P =.041 and r(S) = -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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adult
  • Area Under Curve
  • Bile / metabolism
  • Biological Transport, Active / drug effects
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / blood
  • Cardiotonic Agents / pharmacokinetics*
  • Cardiotonic Agents / urine
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism
  • Digoxin / administration & dosage
  • Digoxin / blood
  • Digoxin / pharmacokinetics*
  • Digoxin / urine
  • Dose-Response Relationship, Drug
  • Fluorescence Polarization Immunoassay
  • Humans
  • Infusions, Intravenous
  • Intestinal Absorption
  • Jejunum / metabolism*
  • Jejunum / physiology
  • Male
  • Quinidine
  • Reference Values
  • Rifampin


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Cardiotonic Agents
  • Digoxin
  • Cytochrome P-450 Enzyme System
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • Quinidine
  • Rifampin