P-glycoprotein-mediated intestinal and biliary digoxin transport in humans.
OBJECTIVE
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).


CONCLUSIONS
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.
Drescher
Siegfried
S
Dr Margarete Fischer-Bosch Institute of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany. siegfried.drescher@ikp-stuttgart.de
Glaeser
Hartmut
H
Mürdter
Thomas
T
Hitzl
Monika
M
Eichelbaum
Michel
M
Fromm
Martin F
MF
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004077:Digoxin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004305:Dose-Response Relationship, Drug; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D007262:Infusions, Intravenous; D007408:Intestinal Absorption; D007583:Jejunum / Q000378:metabolism* / Q000502:physiology; D008297:Male; D011802:Quinidine; D012016:Reference Values; D012293:Rifampin
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D011802:Quinidine; D012293:Rifampin