CONTRIBUTION OF THE MURINE MDR1A P-GLYCOPROTEIN TO HEPATOBILIARY AND INTESTINAL ELIMINATION OF CATIONIC DRUGS AS MEASURED IN MICE WITH AN MDR1A GENE DISRUPTION

In the mouse, both the mdr1a and the mdr1b gene encode drug-transporti ng P-glycoproteins, The mdr1a P-glycoprotein is expressed in epithelia l cells of, among others, the liver and the intestine, Furthermore, th e mdr1b gene product is found in the liver but is not detectable in th e intestine, To establish the potential involvement of P-glycoprotein in the elimination of cationic amphiphilic drugs from the body, we inv estigated biliary, intestinal, and urinary excretion in mice with a ho mozygous disruption of the mdr1a gene (mdr1a(-/-) mice). These mice ar e fully viable under laboratory conditions and have normal bile flow C umulative 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 th e wild-type animals: tri-n-butylmethylammonium (TBuMA), 0.7% versus 2. 1%; azidoprocainamide methoiodide (APM), 3.8% versus 7.6%; and vecuron ium, 22.7% versus 41.3%, The luminal secretion of both TBuMA and APM i n 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 w ild-type) in mdr1a(-/-) mice. Thus mdr1a P-glycoprotein contributes su bstantially to the removal of a nide variety of cationic agents from t he body through intestinal and hepatobiliary secretion, but it evident ly acts in concert with other transport system(s), These processes pro bably provide a protective mechanism limiting the overall rate of abso rption as well as the bioavailability of potentially toxic organic ami nes.