ATP‐dependent transport of amphiphilic cations across the hepatocyte canalicular membrane mediated by <i>mdr1</i> P‐glycoprotein

Müller, Michael; Mayer, R; Hero, Ulrike; Keppler, Dietrich

doi:10.1016/0014-5793(94)80312-9

Cited by 74 publications

(81 citation statements)

References 29 publications

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“…On the basis of in vitro findings, both ATP-dependent and ATP-independent transport processes have been postulated to play a role in the excretion of cationic drugs into bile. [16][17][18] Similar observations have been made with regard to renal drug secretion. In vitro and in vivo studies indicate that P-glycoprotein is also involved in drug secretion at the level of the proximal tubular cells.…”

supporting

confidence: 64%

“…18,47 The [ 3 H]APDA biliary excretion rate was somewhat reduced in mdr1a(Ϫ/Ϫ) mice compared with wild-type mice (Fig. 4).…”

Section: Resultsmentioning

confidence: 94%

“…16,46 However, in the cases of the above-mentioned drugs and other lipophilic anticancer drugs, substantial aspecific binding may obscure the interpretation of such vesicle studies. In 1994, Mü ller et al showed ATP-dependent transport of the less lipophilic model cationic compounds, APDA and pentylquinidine, both in canalicular liver plasma membrane vesicles 18 and in vesicles obtained from insect cells transfected with rat mdr1b. 47 Consequently, less lipophilic drugs probably also can be recognized by P-glycoprotein, and this transporter could contribute to bile secretion of a wide variety of (cationic) drugs.…”

Section: Discussionmentioning

confidence: 99%

“…In 1994, Mü ller et al showed ATP-dependent transport of the less lipophilic model cationic compounds, APDA and pentylquinidine, both in canalicular liver plasma membrane vesicles 18 and in vesicles obtained from insect cells transfected with rat mdr1b. 47 Consequently, less lipophilic drugs probably also can be recognized by P-glycoprotein, and this transporter could contribute to bile secretion of a wide variety of (cationic) drugs. 18,47 In the present study, we show that disruption of the mdr1a gene leads to a significant change in the elimination of various cationic drugs in mice.…”

Section: Discussionmentioning

confidence: 99%

“…Tri-n-butylmethylammonium (TBuMA) and [ 3 H]TBuMA were synthesized in our laboratory, according to the procedures described by Neef et al 25 Azidoprocainamide methoiodide (APM) was synthesized according to the method of Mol et al 26 Azopentyldeoxyajmalinium (APDA) was obtained from Dr. G. Kurz (Freiburg, Germany). 18 Hypnorm was purchased from Janssen Pharmaceuticals (Tilburg, The Netherlands), and diazepam was from Dumex B.V. (Hilversum, The Netherlands). Deionized water was obtained using the Milli-Q Plus System (Millipore, Milford, MA).…”

Section: Methodsmentioning

confidence: 99%

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

Smit¹,

Schinkel

Müller³

et al. 1998

Hepatology

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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 wide 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

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supporting

confidence: 64%

“…18,47 The [ 3 H]APDA biliary excretion rate was somewhat reduced in mdr1a(Ϫ/Ϫ) mice compared with wild-type mice (Fig. 4).…”

Section: Resultsmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

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

Smit¹,

Schinkel

Müller³

et al. 1998

Hepatology

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Bile Formation and Secretion

Boyer

2013

Comprehensive Physiology

681

602

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Bile is a unique and vital aqueous secretion of the liver that is formed by the hepatocyte and modified down stream by absorptive and secretory properties of the bile duct epithelium. Approximately 5% of bile consists of organic and inorganic solutes of considerable complexity. The bile-secretory unit consists of a canalicular network which is formed by the apical membrane of adjacent hepatocytes and sealed by tight junctions. The bile canaliculi (~1 μm in diameter) conduct the flow of bile countercurrent to the direction of portal blood flow and connect with the canal of Hering and bile ducts which progressively increase in diameter and complexity prior to the entry of bile into the gallbladder, common bile duct, and intestine. Canalicular bile secretion is determined by both bile salt-dependent and independent transport systems which are localized at the apical membrane of the hepatocyte and largely consist of a series of adenosine triphosphate-binding cassette transport proteins that function as export pumps for bile salts and other organic solutes. These transporters create osmotic gradients within the bile canalicular lumen that provide the driving force for movement of fluid into the lumen via aquaporins. Species vary with respect to the relative amounts of bile salt-dependent and independent canalicular flow and cholangiocyte secretion which is highly regulated by hormones, second messengers, and signal transduction pathways. Most determinants of bile secretion are now characterized at the molecular level in animal models and in man. Genetic mutations serve to illuminate many of their functions.

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