title: Increased absorption of digoxin from the human jejunum due to inhibition of intestinal transporter-mediated efflux.
abstract: OBJECTIVE
  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.
authors: Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.
authors: Svitlana
authors: S
authors: Igel
authors: Siegfried
authors: S
authors: Drescher
authors: Thomas
authors: T
authors: Mürdter
authors: Ute
authors: U
authors: Hofmann
authors: Georg
authors: G
authors: Heinkele
authors: Heike
authors: H
authors: Tegude
authors: Hartmut
authors: H
authors: Glaeser
authors: Stefanie S
authors: SS
authors: Brenner
authors: Andrew A
authors: AA
authors: Somogyi
authors: Taher
authors: T
authors: Omari
authors: Christian
authors: C
authors: Schäfer
authors: Michel
authors: M
authors: Eichelbaum
authors: Martin F
authors: MF
authors: Fromm
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000284:Administration, Oral; D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000493:pharmacokinetics; D000983:Antipyrine / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D001693:Biological Transport, Active / Q000187:drug effects; D004077:Digoxin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D020895:Enterocytes / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007583:Jejunum / Q000166:cytology / Q000378:metabolism*; D008297:Male; D021381:Protein Transport / Q000187:drug effects; D011802:Quinidine / Q000008:administration & dosage / Q000493:pharmacokinetics; D015262:Xenobiotics / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004791:Enzyme Inhibitors; D015262:Xenobiotics; D004077:Digoxin; D011802:Quinidine; D000983:Antipyrine
references: Biochem Biophys Res Commun. 1992 Nov 30;189(1):551-7
references: 1360207
references: Clin Pharmacol Ther. 2001 Sep;70(3):217-27
references: 11557909
references: Clin Pharmacol Ther. 2003 Mar;73(3):223-31
references: 12621387
references: Gut. 2003 Dec;52(12):1788-95
references: 14633964
references: Gastroenterology. 2001 Feb;120(2):525-33
references: 11159893
references: Pharm Res. 1994 Nov;11(11):1540-7
references: 7870668
references: Clin Pharmacol Ther. 2007 Mar;81(3):362-70
references: 17215845
references: Br J Clin Pharmacol. 2002 May;53(5):526-34
references: 11994059
references: Clin Pharmacol Ther. 2006 May;79(5):449-60
references: 16678547
references: J Clin Invest. 1999 Jul;104(2):147-53
references: 10411543
references: J Pharmacol Exp Ther. 2003 Aug;306(2):703-8
references: 12724351
references: Clin Pharmacol Ther. 2004 Sep;76(3):230-8
references: 15371984
references: J Pharmacokinet Biopharm. 1979 Jun;7(3):233-48
references: 480146
references: N Engl J Med. 1979 Aug 23;301(8):400-4
references: 460341
references: Clin Pharmacol Ther. 2000 Oct;68(4):345-55
references: 11061574
references: Adv Drug Deliv Rev. 1997 Sep 15;27(2-3):161-170
references: 10837556
references: J Clin Invest. 1995 Oct;96(4):1698-705
references: 7560060
references: Circulation. 1999 Feb 2;99(4):552-7
references: 9927403
references: J Clin Invest. 1998 Jan 15;101(2):289-94
references: 9435299
references: Trends Pharmacol Sci. 2004 Aug;25(8):423-9
references: 15276711
references: Drug Metab Dispos. 2006 Sep;34(9):1468-79
references: 16751264
references: Cancer Res. 1999 Aug 15;59(16):3944-8
references: 10463589
references: Br J Clin Pharmacol. 2003 Feb;55(2):182-90
references: 12580990
references: Curr Drug Metab. 2004 Feb;5(1):109-24
references: 14965254
references: Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3569-74
references: 14993604