Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with an mdr1a gene disruption

J.W Smit, A.H Schinkel, M Muller, B Weert, D.K F Meijer

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Abstract

In the mouse, both the mdr1a and the mdr1b gene encode drug-transporting P-glycoproteins, The mdr1a P-glycoprotein is expressed in epithelial cells of, among others, the liver and the intestine, Furthermore, the mdr1b gene product is found in the liver but is not detectable in the intestine, To establish the potential involvement of P-glycoprotein in the elimination of cationic amphiphilic drugs from the body, we investigated biliary, intestinal, and urinary excretion in mice with a homozygous disruption of the mdr1a gene (mdr1a(-/-) mice). These mice are fully viable under laboratory conditions and have normal bile flow Cumulative biliary excretion (expressed as percent of the intravenously administered dose excreted over a 1-hour period) of several cationic compounds was decreased as follows in mdr1a(-/-) mice compared with the wild-type animals: tri-n-butylmethylammonium (TBuMA), 0.7% versus 2.1%; azidoprocainamide methoiodide (APM), 3.8% versus 7.6%; and vecuronium, 22.7% versus 41.3%, The luminal secretion of both TBuMA and APM in the small intestine was profoundly decreased, respectively 4.6-fold (1.8% vs, 8.2% in the wild-type) and 7.9-fold (1.6% vs, 10.3% in the wild-type) in mdr1a(-/-) mice. Thus mdr1a P-glycoprotein contributes substantially to the removal of a nide variety of cationic agents from the body through intestinal and hepatobiliary secretion, but it evidently acts in concert with other transport system(s), These processes probably provide a protective mechanism limiting the overall rate of absorption as well as the bioavailability of potentially toxic organic amines.

Original languageEnglish
Pages (from-to)1056 - 1063
Number of pages8
JournalHepatology
Volume27
Issue number4
Publication statusPublished - Apr-1998
Event47th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases - , Israel
Duration: 8-Nov-199612-Nov-1996

Keywords

  • STRUCTURE-PHARMACOKINETICS RELATIONSHIP
  • QUATERNARY AMMONIUM-COMPOUNDS
  • ORGANIC ANION TRANSPORTER
  • PLASMA-MEMBRANE VESICLES
  • BRUSH-BORDER MEMBRANES
  • BLOOD-BRAIN-BARRIER
  • PERFUSED RAT-KIDNEY
  • CELL LINE LLC-PK1
  • BILIARY-EXCRETION
  • ANTIPORT SYSTEM

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