CONTRIBUTION OF THE MURINE MDR1A P-GLYCOPROTEIN TO HEPATOBILIARY AND INTESTINAL ELIMINATION OF CATIONIC DRUGS AS MEASURED IN MICE WITH AN MDR1A GENE DISRUPTION
Jw. Smit et al., CONTRIBUTION OF THE MURINE MDR1A P-GLYCOPROTEIN TO HEPATOBILIARY AND INTESTINAL ELIMINATION OF CATIONIC DRUGS AS MEASURED IN MICE WITH AN MDR1A GENE DISRUPTION, Hepatology, 27(4), 1998, pp. 1056-1063
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.