Induction of hepatic P-glycoprotein enhances biliary excretion of vincristine in rats

Watanabe, Tohru; Suzuki, Hiroshi; Sawada, Yasufumi; Naito, Mikihiko; Tsuruo, Takashi; Inaba, Makoto; Hanano, Manabu; Sugiyama, Yuichi

doi:10.1016/0168-8278(95)80203-7

Cited by 33 publications

(27 citation statements)

References 24 publications

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“…PTZ treatment results in an increased expression of P-GP [26]. This may imply that BSP is a substrate of P-GP, although this might represent a minor pathway for the anionic dye [35].…”

Section: Discussionmentioning

confidence: 99%

“…VLB clearly inhibited biliary EM excretion, and PTZ treatment, which increases the canalicular P-GP level [26], significantly increased biliary EM excretion. Since VLB did not affect EM blood clearance, this compound is considered not to alter the influx of EM into hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

“…dissolved in 200 Ìl 0.9% NaCl) was intraperitoneally injected 30 min before EM injection [25], and PTZ (5 mg/100 g b.w. dissolved in 0.28 ml corn oil) was intraperitoneally injected for 3 days prior to the experiments [26].…”

Section: Methodsmentioning

confidence: 99%

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Effects of Organic Anions and Vinblastine on Biliary Excretion of Erythromycin in Rats

Sato

Takikawa²,

Yamanaka³

1999

Pharmacology

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Since little is known about the mechanism of biliary excretion of cationic drugs, biliary excretion of erythromycin was studied in rats. Infusion of sulfobromophthalein and taurocholate significantly decreased biliary erythromycin excretion, whereas infusion of dibromosulfophthalein, cefpiramide, ursodeoxycholate-3-O-glucuronide and taurolithocholate-3-sulfate had no effect on biliary excretion of erythromycin. Vinblastine significantly inhibited biliary erythromycin excretion. Phenothiazine treatment significantly increased biliary erythromycin excretion. However, erythromycin infusion did not affect biliary vinblastine excretion. These findings indicate a multiplicity of biliary excretory pathways for organic cations; at least one additonal pathway may exist for organic cations apart from P-glycoprotein.

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“…PTZ treatment results in an increased expression of P-GP [26]. This may imply that BSP is a substrate of P-GP, although this might represent a minor pathway for the anionic dye [35].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Effects of Organic Anions and Vinblastine on Biliary Excretion of Erythromycin in Rats

Sato

Takikawa²,

Yamanaka³

1999

Pharmacology

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“…16 These studies were performed with rather hydrophobic anticancer drugs such as daunomycin and vincristine. 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.…”

Section: Discussionmentioning

confidence: 99%

Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with anmdr1agene 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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“…Certain hepatomas and hepatoma-derived cell lines demonstrate up-regulation of MDR1, mdr1a, and 1b. 55,56 Drug exposure to acetylaminofluorene, 55 3-methylcholanthrene, 57 phenothiazines, 58 and verapamil, 59 all mdr1 substrates, increase mdr1 expression and, in some instances, enhance mdr1 substrate excretion. 58,60 Mdr1a and 1b expression at the canalicular domain is also increased by exposure FIG.…”

Section: Discussionmentioning

confidence: 99%

Hepatic sequestration and modulation of the canalicular transport of the organic cation, daunorubicin, in the rat

Hayes¹,

Soroka²,

Rios-Velez³

et al. 1999

Hepatology

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In contrast to organic anions, substrates for the canalicular mdr1a and b are usually organic cations and are often sequestered in high concentrations in intracellular acidic compartments. Because many of these compounds are therapeutic agents, we investigated if their sequestration could be regulated. We used isolated perfused rat liver (IPRL), isolated rat hepatocyte couplets (IRHC), and WIF-B cells to study the cellular localization and biliary excretion of the fluorescent cation, daunorubicin (DNR). Despite rapid (within 15 minutes) and efficient (G90%) cellular uptake in the IPRL, only Ϸ10% of the dose administered A major function of the liver is the uptake and biliary excretion of a variety of lipophilic compounds, including endogenous substances such as bilirubin, and exogenous substances such as xenobiotics, drugs, and toxins. Distinct transport proteins are localized on the basolateral and canalicular domains of the hepatocyte to perform this function. 1,2 Many of these transporters have been cloned from rodent and human liver, and most of the canalicular transporters are members of the adenosine triphosphate (ATP) binding cassette super gene family. [3][4][5] These transporters include the multidrug resistance-associated protein, mrp2 or cMOAT, which excretes a variety of amphipathic organic anions 6-8 ; the canalicular bile salt excretory pump (bsep), which promotes ATP-dependent transport of bile salts into bile 9-11 and may be identical with spgp, the sister of P-glycoprotein 12 ; and the P-glycoproteins, mdr1a and 1b, whose endogenous substrates are not known but which transport a variety of organic cations and toxic substances into bile. [13][14][15][16][17] Overexpression of mdr1a and b can occur in cancer cell lines and thereby contribute to resistance to a variety of chemotherapeutic agents. 18 Previous studies have established that some of these excretory transport systems are highly regulated rather than constitutive functions of the hepatocyte, and that compounds such as N 6 ,2Ј-O-dibutyryl-adenosine 3Ј,5Јcyclic monophosphate (DBcAMP) and bile salts are capable of up-regulating their transport capacity. [19][20][21][22] In contrast, inhibitors of microtubule function down-regulate these transport processes. 19,21,23 This type of regulation has been demonstrated for the fluorescent bsep substrate, cholyglycylamidofluorescein (CGamF), and for the mrp2 substrate, glutathione-Smethylfluorescein. 20,21 These findings have led to the conclusion that the plasma membrane transport proteins may also reside on intracellular pericanalicular vesicles, and that apical transport capacity may be regulated by the insertion and/or retrieval of these vesicles to or from the apical canalicular membrane. 21,22,24,25 In the present study, we examined whether the canalicular excretion of the mdr1 transport system can be regulated using the fluorescent mdr1 substrate, daunorubicin (DNR). DNR is a naturally fluorescent organic cation that is widely used as an antineoplastic agent. [26][27][28] Thus, understanding ...

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Induction of hepatic P-glycoprotein enhances biliary excretion of vincristine in rats

Cited by 33 publications

References 24 publications

Effects of Organic Anions and Vinblastine on Biliary Excretion of Erythromycin in Rats

Effects of Organic Anions and Vinblastine on Biliary Excretion of Erythromycin in Rats

Contribution of the murine mdr1a P-glycoprotein to hepatobiliary and intestinal elimination of cationic drugs as measured in mice with anmdr1agene disruption

Hepatic sequestration and modulation of the canalicular transport of the organic cation, daunorubicin, in the rat

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