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.
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