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Biliary Excretion

The Experts below are selected from a list of 153 Experts worldwide ranked by ideXlab platform

Kim L. R. Brouwer – 1st expert on this subject based on the ideXlab platform

  • Apparent differences in mechanisms of harmol sulfate Biliary Excretion in mice and rats.
    Drug Metabolism and Disposition, 2008
    Co-Authors: Maciej J. Zamek-gliszczynski, Keith Hoffmaster, Ken Ichi Nezasa, Kim L. R. Brouwer

    Abstract:

    Previous experiments demonstrated that the Biliary Excretion of harmol sulfate (HS) was mediated by breast cancer resistance protein (Bcrp) and not by multidrug resistance-associated protein (Mrp)2 or P-glycoprotein in mice. However, recent reports suggested that species differences in hepatic canalicular transport mechanisms for a given substrate exist between mice and rats. In the present study, Biliary Excretion of HS was examined in perfused livers from mice and rats in the absence or presence of the P-glycoprotein and Bcrp inhibitor N -(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide (GF120918). As expected, in mouse liver perfusions, the Biliary Excretion of HS was decreased ∼3.5-fold by GF120918, consistent with previous reports of Bcrp-mediated HS Biliary Excretion. However, despite sufficient hepatic unbound concentrations of GF120918 to achieve extensive inhibition of Bcrp, the Biliary Excretion of HS was not decreased significantly in wild-type (50 ± 12 versus 41 ± 6%) or TR – (18 ± 2 versus 16 ± 3%) Wistar rats. In summary, Biliary Excretion of HS was mediated by a GF120918-sensitive mechanism in mice, previously elucidated as Bcrp. In contrast, the pathway responsible for HS Biliary Excretion in rats was not impaired by GF120918. Thus, transport mechanism(s) responsible for harmol sulfate Biliary Excretion appear to differ between mice and rats.

  • roles of p glycoprotein bcrp and mrp2 in Biliary Excretion of spiramycin in mice
    Antimicrobial Agents and Chemotherapy, 2007
    Co-Authors: Xianbin Tian, Jun Li, Maciej J Zamekgliszczynski, Arlene S Bridges, Peijin Zhang, Nita J Patel, Thomas J Raub, Gary M Pollack, Kim L. R. Brouwer

    Abstract:

    The multidrug resistance proteins P-glycoprotein (P-gp), breast cancer resistance protein (Bcrp), and multidrug resistance-associated protein 2 (Mrp2) are the three major canalicular transport proteins responsible for the Biliary Excretion of most drugs and metabolites. Previous in vitro studies demonstrated that P-gp transported macrolide antibiotics, including spiramycin, which is eliminated primarily by Biliary Excretion. Bcrp was proposed to be the primary pathway for spiramycin secretion into breast milk. In the present study, the contributions of P-gp, Bcrp, and Mrp2 to the Biliary Excretion of spiramycin were examined in single-pass perfused livers of male C57BL/6 wild-type, Bcrp-knockout, and Mrp2-knockout mice in the presence or absence of GF120918 (GW918), a P-gp and Bcrp inhibitor. Spiramycin was infused to achieve steady-state conditions, followed by a washout period, and parameters governing spiramycin hepatoBiliary disposition were recovered by using pharmacokinetic modeling. In the absence of GW918, the rate constant governing spiramycin Biliary Excretion was decreased in Mrp2 − knockout mice (0.0013 ± 0.0009 min −1 ) relative to wild-type mice (0.0124 ± 0.0096 min −1 ). These data are consistent with the ∼8-fold decrease in the recovery of spiramycin in the bile of Mrp2-knockout mice and suggest that Mrp2 is the major canalicular transport protein responsible for spiramycin Biliary Excretion. Interestingly, Biliary recovery of spiramycin in Bcrp-knockout mice was increased in both the absence and presence of GW918 compared to wild-type mice. GW918 significantly decreased the rate constant for spiramycin Biliary Excretion and the rate constant for basolateral efflux of spiramycin. In conclusion, the Biliary Excretion of spiramycin in mice is mediated primarily by Mrp2 with a modest P-gp component.

  • p glycoprotein mediated in vitro Biliary Excretion in sandwich cultured rat hepatocytes
    Drug Metabolism and Disposition, 2001
    Co-Authors: Pieter Annaert, Ryan Z Turncliff, Catherine Booth, Dhiren R Thakker, Kim L. R. Brouwer

    Abstract:

    Recently, sandwich-cultured (SC) rat hepatocytes have been used as an in vitro model to assess Biliary Excretion of drugs and xenobiotics. The purpose of the present study was to validate the use of SC rat hepatocytes for the in vitro assessment of P-glycoprotein (P-gp)-mediated Biliary drug Excretion. The specific and fluorescent P-gp substrate rhodamine 123 (Rh123) and the P-gp substrate digoxin were selected as model compounds. Rh123 and digoxin accumulation and Rh123 efflux under standard and Ca 2+ -free conditions were quantified in SC rat hepatocytes to determine substrate secretion into canalicular networks in vitro. The major role of P-gp in the Biliary Excretion of these compounds was confirmed by inhibition experiments with the potent P-gp inhibitor GF120918. Hepatocyte culture conditions, including media type and time in culture, significantly affected Rh123 Biliary Excretion. P-gp expression, as assessed by Western blot, was increased with culture time. Dexamethasone (an in vivo inducer of P-gp) concentrations ranging from 0.01 to 1 μM in the cell culture medium did not influence P-gp expression or Rh123 Biliary Excretion. Rh123 and digoxin Biliary clearance values, predicted from SC rat hepatocyte data, were consistent with values reported in vivo and in isolated perfused rat liver studies. In conclusion, the results of this study demonstrate the utility of SC rat hepatocytes as an in vitro model to study and predict the Biliary Excretion of P-gp substrates.

Yuichi Sugiyama – 2nd expert on this subject based on the ideXlab platform

  • involvement of breast cancer resistance protein abcg2 in the Biliary Excretion mechanism of fluoroquinolones
    Drug Metabolism and Disposition, 2007
    Co-Authors: Tomohiro Ando, Hiroyuki Kusuhara, Gracia Merino, A I Alvarez, Alfred H Schinkel, Yuichi Sugiyama

    Abstract:

    Fluoroquinolones are effective antibiotics for the treatment of bile duct infections. It has been shown that the Biliary Excretion of grepafloxacin is partly accounted for by multidrug resistance-associated protein 2 (MRP2/ ABCC2 ), whereas neither MRP2 nor P-glycoprotein is involved in the Biliary Excretion of ulifloxacin. In the present study, we examined the involvement of breast cancer resistance protein (BCRP/ ABCG2 ) in the Biliary Excretion of fluoroquinolones (grepafloxacin, ulifloxacin, ciprofloxacin, and ofloxacin). In Madin-Darby canine kidney II cells expressing human BCRP or mouse Bcrp, the basal-to-apical transport of grepafloxacin and ulifloxacin was greater than that of the mock control, which was inhibited by a BCRP inhibitor, 3-(6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12 a -octahydropyrazino[1′,2′:1,6]pyrido[3,4- b ]indol-3-yl)-propionic acid tert -butyl ester (Ko143). Plasma and bile concentrations of fluoroquinolones were determined in wild-type and Bcrp(-/-) mice after i.v. bolus injection. The cumulative Biliary Excretion of fluoroquinolones was significantly reduced in Bcrp(-/-) mice, resulting in a reduction of the Biliary Excretion clearances to 86, 50, 40, and 16 of the control values, for ciprofloxacin, grepafloxacin, ofloxacin, and ulifloxacin, respectively. Preinfusion of sulfobromophthalein significantly inhibited the Biliary Excretion of grepafloxacin in Bcrp(-/-) mice. There was no change in the tissue/plasma concentration ratios of fluoroquinolones in the liver or brain, whereas those in the kidney were increased 3.6- and 1.5-fold for ciprofloxacin and grepafloxacin, respectively, in Bcrp(-/-) mice but were unchanged for ofloxacin and ulifloxacin. The present study shows that BCRP mediates the Biliary Excretion of fluoroquinolones and suggests that it is also involved in the tubular secretion of ciprofloxacin and grepafloxacin.

  • involvement of bcrp abcg2 in the Biliary Excretion of pitavastatin
    Molecular Pharmacology, 2005
    Co-Authors: Masaru Hirano, Kazuya Maeda, Soichiro Matsushima, Yoshitane Nozaki, Hiroyuki Kusuhara, Yuichi Sugiyama

    Abstract:

    Pitavastatin, a novel potent 3-hydroxymethylglutaryl coenzyme A reductase inhibitor, is distributed selectively to the liver and excreted into bile in unchanged form in rats. We reported previously that the hepatic uptake is mainly mediated by organic anion transporting polypeptide (OATP) 1B1, whereas the Biliary Excretion mechanism remains to be clarified. In the present study, we investigated the role of breast cancer resistance protein (BCRP) in the Biliary Excretion of pitavastatin. The ATP-dependent uptake of pitavastatin by human and mouse BCRP-expressing membrane vesicles was significantly higher compared with that by control vesicles with Km values of 5.73 and 4.77 μM, respectively. The Biliary Excretion clearance of pitavastatin in Bcrp1(-/-) mice was decreased to one-tenth of that in control mice. The Biliary Excretion of pitavastatin was unchanged between control and Eisai hyperbilirubinemic rats, indicating a minor contribution of multidrug resistance-associated protein (Mrp) 2. This observation differs radically from that for a more hydrophilic statin, pravastatin, of which Biliary Excretion is largely mediated by Mrp2. These data suggest that the Biliary clearance of pitavastatin can be largely accounted for by BCRP in mice. In the case of humans, transcellular transport of pitavastatin was determined in the Madin-Darby canine kidney II cells expressing OATP1B1 and human canalicular efflux transporters. A significant basal-to-apical transport of pitavastatin was observed in OATP1B1/MDR1 and OATP1B1/MRP2 double transfectants as well as OATP1B1/BCRP double transfectants, implying the involvement of multiple transporters in the Biliary Excretion of pitavastatin in humans. This is in contrast to a previous belief that the Biliary Excretion of statins is mediated mainly by MRP2.

  • Mechanism of the tissue distribution and Biliary Excretion of the cyclic peptide octreotide.
    Journal of Pharmacology and Experimental Therapeutics, 1996
    Co-Authors: Tadashi Yamada, Kayoko Niinuma, Michel Lemaire, Tetsuya Terasaki, Yuichi Sugiyama

    Abstract:

    The hepatoBiliary transport and tissue distribution of the cationic cyclooctapeptide octreotide were studies at steady state after its infusion, at various rates, in rats. After an increase in steady-state plasma concentration, marked decrease in the tissue to plasma concentration ratio was observed only in pancreas, the target organ of octreotide. A marked decrease in the Biliary Excretion clearance, defined with respect to the concentration in the liver, was also observed, suggesting that a transport carrier was involved in the Biliary Excretion. The plasma elimination and Biliary Excretion profiles of octreotide were determined in Eisai hyperbilirubinemic rats (EHBR), which have an hereditary defect of the active transport carrier for organic anions in bile canalicular membranes. Although Biliary Excretion of octreotide was significantly reduced in EHBR, compared with normal Sprague-Dawley rats, no difference was observed in Biliary Excretion clearance, defined with respect to the concentration in the liver, between Sprague-Dawley rats and EHBR. On the other hand, the liver to plasma concentration ratio in EHBR fell to half that in Sprague-Dawley rats. These results suggest that the decreased Biliary Excretion of octreotide in EHBR is due not to reduced Biliary Excretion ability but to reduced hepatic uptake of octreotide. We studied in vitro transport using bile canalicular membrane vesicles. A significant increase in the transport of octreotide by bile canalicular membrane vesicles was observed in the presence of ATP, and the estimated kinetic parameters K(m) and Vmax were 6.5 microM and 370 pmol/min/mg of protein, respectively. Similar ATP-dependent uptake was observed in bile canalicular membrane vesicles prepared from EHBR. We concluded that the Biliary Excretion of octreotide is by ATP-dependent primary active transport and that the carrier system for octreotide differs from the so-called “canalicular multispecific organic anion transporter,” which is absent in EHBR.

Dong Li – 3rd expert on this subject based on the ideXlab platform

  • structure pharmacokinetic relationship of in vivo rat Biliary Excretion
    Biopharmaceutics & Drug Disposition, 2010
    Co-Authors: Yue Chen, Kimberly Okeefe Cameron, Angel Guzmanperez, David Austen Perry, Dong Li

    Abstract:

    Accurately measuring and predicting Biliary Excretion would be extremely valuable in evaluating the contribution of Biliary Excretion to the total systemic clearance, understanding potential mechanisms of hepatoBiliary toxicity as well as potentials for drug–drug interactions in drug discovery. In this study, in vivo rat Biliary Excretion of drug-like molecules was measured using bile duct cannulated rats. Literature Biliary Excretion data with similar experimental conditions were collected. A predictive quantitative structure–pharmacokinetic relationship (QSPR) model was developed using genetic algorithm guided principal component regression analysis and 2D molecular descriptors. In the derived model, hydrophobicity expressed with calculated distribution coefficients (cLogD) is the most important molecular property correlating Biliary Excretion. The derived model has been validated using literature data, and should be useful in estimating Biliary Excretion potentials of molecules in drug discovery. Copyright © 2009 John Wiley & Sons, Ltd.

  • Structure–pharmacokinetic relationship of in vivo rat Biliary Excretion
    Biopharmaceutics & Drug Disposition, 2009
    Co-Authors: Yue Chen, Kimberly Okeefe Cameron, David Austen Perry, Angel Guzman-perez, Dong Li

    Abstract:

    Accurately measuring and predicting Biliary Excretion would be extremely valuable in evaluating the contribution of Biliary Excretion to the total systemic clearance, understanding potential mechanisms of hepatoBiliary toxicity as well as potentials for drug–drug interactions in drug discovery. In this study, in vivo rat Biliary Excretion of drug-like molecules was measured using bile duct cannulated rats. Literature Biliary Excretion data with similar experimental conditions were collected. A predictive quantitative structure–pharmacokinetic relationship (QSPR) model was developed using genetic algorithm guided principal component regression analysis and 2D molecular descriptors. In the derived model, hydrophobicity expressed with calculated distribution coefficients (cLogD) is the most important molecular property correlating Biliary Excretion. The derived model has been validated using literature data, and should be useful in estimating Biliary Excretion potentials of molecules in drug discovery. Copyright © 2009 John Wiley & Sons, Ltd.