The Experts below are selected from a list of 153 Experts worldwide ranked by ideXlab platform
Kim L. R. Brouwer - One of the best experts 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, 2008Co-Authors: Maciej J. Zamek-gliszczynski, Keith Hoffmaster, Ken Ichi Nezasa, Kim L. R. BrouwerAbstract: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, 2007Co-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. BrouwerAbstract: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, 2001Co-Authors: Pieter Annaert, Ryan Z Turncliff, Catherine Booth, Dhiren R Thakker, Kim L. R. BrouwerAbstract: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.
-
correlation of Biliary Excretion in sandwich cultured rat hepatocytes and in vivo in rats
Drug Metabolism and Disposition, 1999Co-Authors: Jack P Chism, Edward L Lecluyse, Kenneth R Brouwer, Kim L. R. BrouwerAbstract:The relationship between Biliary Excretion in sandwich-cultured rat hepatocytes and in vivo in rats was examined. The Biliary Excretion of seven model substrates in 96-h sandwich-cultured rat hepatocytes was determined by differential cumulative uptake of substrate in the monolayers preincubated in standard buffer (intact bile canaliculi) and Ca2+-free buffer (disrupted bile canaliculi). Biliary Excretion in vivo was quantitated in bile duct-cannulated rats. The Biliary Excretion index of model substrates, equivalent to the percentage of retained substrate in the canalicular networks, was consistent with the percentage of the dose excreted in bile from in vivo experiments. The in vitro Biliary clearance of inulin, salicylate, methotrexate, [d-pen2,5]enkephalin, and taurocholate, calculated as the ratio of the amount excreted into the bile canalicular networks and the area under the incubation medium concentration-time profile (∼0, ∼0, 4.1 ± 1.0, 12.6 ± 2.2, and 56.2 ± 6.0 ml/min/kg, respectively), correlated with their intrinsic in vivo Biliary clearance (0.04, 0, 17.3, 34.4, and 116.9 ml/min/kg, respectively; r2 = 0.99). The model compound 264W94 was not excreted in bile either in vivo or in vitro. The glucuronide conjugate of 2169W94, theO-demethylated metabolite of 264W94, was excreted into bile in vitro when 2169W94, but not 264W94, was incubated with the monolayers; 2169W94 glucuronide undergoes extensive Biliary Excretion after administration of 264W94 or 2169W94 in vivo. Biliary Excretion in long-term sandwich-cultured rat hepatocytes correlates with in vivo Biliary Excretion. The study of Biliary Excretion of metabolites in the hepatocyte monolayers requires consideration of the status of metabolic activities.
Yuichi Sugiyama - One of the best experts 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, 2007Co-Authors: Tomohiro Ando, Hiroyuki Kusuhara, Gracia Merino, A I Alvarez, Alfred H Schinkel, Yuichi SugiyamaAbstract: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, 2005Co-Authors: Masaru Hirano, Kazuya Maeda, Soichiro Matsushima, Yoshitane Nozaki, Hiroyuki Kusuhara, Yuichi SugiyamaAbstract: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, 1996Co-Authors: Tadashi Yamada, Kayoko Niinuma, Michel Lemaire, Tetsuya Terasaki, Yuichi SugiyamaAbstract: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.
-
Biliary Excretion of Glycyrrhizin in Rats: Kinetic Basis for Multiplicity in Bile Canalicular Transport of Organic Anions
Pharmaceutical Research, 1996Co-Authors: Hisafumi Shimamura, Hiroshi Suzuki, Osamu Tagaya, Tohru Horie, Yuichi SugiyamaAbstract:Purpose . To examine the presence of multiplicity for the Biliary Excretion of xenobiotic conjugates, we studied the disposition of glycyrrhizin (GR), which has glucuronide within its molecular structure and has the ability to inhibit the Biliary Excretion of liquiritigenin (LG) glucuronides. Methods . GR was administered intravenously as a bolus to Sprague-Dawley (SD) rats which received an i.v. infusion of inhibitors (dibromo-sulfophthalein (DBSP) and indocyanine green (ICG)) at their transport maximum rates. Biliary Excretion of GR was also examined in Eisai hyperbilirubinemic rats (EHBR), which have a hereditary defect in the canalicular transport system of several organic anions. Results . Infusion of ICG did not affect the Biliary Excretion of GR, whereas infusion of DBSP reduced it significantly. The plasma concentration of GR was increased by DBSP but not by ICG. In EHBR, the Biliary Excretion of GR was severely impaired, resulting in an increase in the plasma concentration of GR. Conclusions . These findings suggest (1) that the Biliary Excretion of GR is mediated by the system which is shared by DBSP and LG glucuronides but not by ICG and (2) that this system is hereditarily defective in EHBR. Together with our previous findings, the multiplicity for the Biliary Excretion of organic anions is shown.
-
Recent advances in carrier-mediated hepatic uptake and Biliary Excretion of xenobiotics
Pharmaceutical Research, 1996Co-Authors: Masayo Yamazaki, Hiroshi Suzuki, Yuichi SugiyamaAbstract:Purpose. Besides renal Excretion, hepatic metabolism and Biliary Excretion are the major pathways involved in the removal of xenobiotics. Recently, for many endogenous and exogenous compounds (including drugs), it has been reported that carrier-mediated transport contributes to hepatic uptake and/ or Biliary Excretion. In particular, primary active transport mechanisms have been shown to be responsible for the Biliary Excretion of anticancer drugs, endogenous bile acids and organic anions including glutathione and glucuronic acid conjugates. Primary active Excretion into bile means the positive removal of xenobiotics from the body, and this elimination process is now designated as “Phase III” (T. Ishikawa, Trends Biochem. Sci., 17, 1992) in the detoxification mechanisms for xenobiotics in addition to Phase I by P-450 and Phase II by conjugation.
Dong Li - One of the best experts on this subject based on the ideXlab platform.
-
structure pharmacokinetic relationship of in vivo rat Biliary Excretion
Biopharmaceutics & Drug Disposition, 2010Co-Authors: Yue Chen, Kimberly Okeefe Cameron, Angel Guzmanperez, David Austen Perry, Dong LiAbstract: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, 2009Co-Authors: Yue Chen, Kimberly Okeefe Cameron, David Austen Perry, Angel Guzman-perez, Dong LiAbstract: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.
Hajime Takikawa - One of the best experts on this subject based on the ideXlab platform.
-
Effect of genipin on the Biliary Excretion of cholephilic compounds in rats
Hepatology Research, 2007Co-Authors: Masaki Mikami, Hajime TakikawaAbstract:AIM: Genipin, a metabolite of geniposide, is reported to stimulate the insertion of multidrug resistance protein 2 (Mrp2) in the bile canalicular membrane, and to cause choleresis by increasing the Biliary Excretion of glutathione, which has been considered to be a substrate of Mrp2. In the present study, the effect of colchicine on the choleretic effect of genipin was investigated. The effect of genipin on the Biliary Excretion of the substrates of bile salt export pump and Mrp2 was also studied. METHODS: After bile duct cannulation into rats, genipin was administered at the rate of 0.2 mumol/min/100 g, and the effect of colchicine pretreatment (0.2 mg/100 g) was examined. Metabolites of genipin in the bile were examined by a thin layer chromatography. Taurocholate (TC), sulfobromophthalein (BSP), and pravastatin were infused at the rate of 1.0, 0.2 and 0.3 mumol/min/100 g, respectively, and the effect of genipin co-administration was examined. RESULTS: Genipin increased bile flow and the Biliary glutathione Excretion, and those increases were not inhibited by colchicine. The Biliary Excretion of genipin glucuronide was less than 10% of the genipin excreted into bile. The Biliary Excretion of TC, BSP, and pravastatin was unchanged by genipin co-administration. CONCLUSION: It was indicated that colchicine-sensitive vesicular transport has no role on the genipin-induced insertion of Mrp2 to the canalicular membrane. Choleresis of genipin is considered to be mainly due to the increased Biliary glutathione Excretion by genipin, not by the Biliary Excretion of glucuronide. TC had no effect on the Biliary glutathione Excretion.
-
Effect of cyclosporin A on the Biliary Excretion of cholephilic compounds in rats.
Hepatology Research, 2006Co-Authors: Masahiro Akashi, Atsushi Tanaka, Hajime TakikawaAbstract:Abstract Cyclosporin A (CsA) is known to cause cholestasis. CsA is reported to competitively inhibit the transport of the substrates of the bile salt export pump (Bsep), multidrug resistance protein 2 (Mrp2) and P-glycoprotein (P-gp) in the canalicular membrane vesicles. However, the inhibitory effect of CsA on various substrates of the canalicular ATP-dependent transporters in vivo is unknown. Therefore, in the present study, the acute effect of CsA on the Biliary Excretion of the substrates of Bsep, Mrp2 and P-gp was examined under the same condition. Ten minutes after the intravenous administration of CsA (25 mg/kg), the Biliary Excretion of various bile acids and organic anions and cations was studied. CsA decreased the Biliary Excretion of tracer amounts of taurocholate, leukotriene C 4 , estradiol-17β-glucuronide, pravastatin, vinblastine and erythromycin. In contrast, the Biliary Excretion of high doses of taurocholate and sulfobromophthalein was only slightly or not inhibited by CsA. In conclusion, CsA may competitively inhibit Biliary Excretion of substrates of Bsep, Mrp2 and P-gp also in vivo, and CsA is considered to inhibit bile acid-dependent bile flow by the competitive inhibition of the canalicular transport of bile acids by Bsep.
-
Biliary Excretion of olmesartan, an anigotensin II receptor antagonist, in the rat.
Journal of Gastroenterology and Hepatology, 2005Co-Authors: Motoe Takayanagi, Naoyo Sano, Hajime TakikawaAbstract:Background and Aim: Olmesartan (RNH-6270) is a newly developed anigotensin II receptor antagonist, and has been reported to be excreted into feces. To examine the mechanism of the Biliary Excretion of olmesartan, we studied its Biliary Excretion in rats. Methods: The Biliary Excretion of olmesartan in Eisai hyperbilirubinemic rats (EHBR), a multidrug resistance protein 2-deficient rat, was compared with control rats, and the effect of organic anions and cation and bile acids on the Biliary Excretion of olmesartan was studied in control rats. Results: The Biliary Excretion of olmesartan was markedly delayed in EHBR. The Biliary Excretion of olmesartan was inhibited by sulfobromophthalein, cefpiramide and pravastatin, but was not inhibited by taurocholate or tauroursodeoxycholate. Vinblastine inhibited and phenothiazine treatment increased the Biliary Excretion of olmesartan. Conclusions: These findings suggest that olmesartan is excreted into the bile mainly by multidrug resistance protein 2 and partly by P-glycoprotein.
-
Effects of colchicine on the maximum Biliary Excretion of cholephilic compounds in rats.
Journal of Gastroenterology and Hepatology, 2004Co-Authors: Hidetaka Tachizawa, Naoyo Sano, Hajime TakikawaAbstract:Background and Aim: Colchicine, an inhibitor of intracellular vesicular transport, has been reported to inhibit the Biliary Excretion of bile acids and organic anions, but the previous findings are controversial. In order to systematically evaluate the effect of colchicine on the Biliary Excretion of cholephilic compounds, we studied the effect of colchicine on the Biliary Excretion of substrates of various canalicular transporters, which were administered at or above the excretory maximum in rats. Methods: Substrates of various canalicular adenosine triphosphate-binding-cassette transporters were infused at or above the rate of maximum Excretion into rats, and the effect of colchicine (0.2 mg/100 g), which was intraperitoneally injected 3 h before, on the Biliary Excretion was studied. Furthermore, the effect of tauroursodeoxycholate (TUDC) co-infusion on the Biliary Excretion of taurocholate (TC) after colchicine treatment was also studied. Results: The Biliary Excretion of TC and cholate administered at the rate of 1 µmol/min/100 g was markedly inhibited by colchicine, whereas that of TUDC was not inhibited even with the infusion rate of 2 µmol/min/100 g. TUDC co-infusion at the rate of 1 µmol/min/100 g increased the Biliary Excretion of TC (1 µmol/min/100 g), which was decreased by the colchicine pretreatment. The Biliary excretory maximum of taurolithocholate-sulfate and sulfobromophthalein, substrates of the multidrug resistance protein 2, of erythromycin, a substrate of the P-glycoprotein, and of indocyanine green were not affected by colchicine. Conclusions: The different excretory maximums of TC and TUDC and the different effect of colchicine on the Excretion of these bile acids are considered to be a result of different regulatory mechanisms of vesicular targeting of the bile salt export pump to the canalicular membrane by these bile acid conjugates. The vesicular targeting of the multidrug resistance protein 2 and the P-glycoprotein to the canalicular membrane is considered to be colchicine insensitive in the absence of bile acid coadministration.
-
Biliary Excretion of azelnidipine, a calcium antagonist, in rats
Journal of Gastroenterology and Hepatology, 2004Co-Authors: Naoko Hanawa, Naoyo Sano, Hajime TakikawaAbstract:Background and Aims: Azelnidipine (CS-905) is a novel dihydropyridine calcium antagonist that is known to be excreted in feces. To examine the mechanism of Biliary Excretion of azelnidipine, the authors studied its Biliary Excretion in Eisai hyperbilirubinuria rats (EHBR), multidrug resistance protein (Mrp)2-deficient rats, and the effect of cholephilic compounds on the Biliary Excretion of azelnidipine in rats. Methods: Radiolabeled azelnidipine was intravenously administered to EHBR and control rats, and the Biliary Excretion of radiolabeled metabolites was studied. Furthermore, the effect of sulfobromophthalein, taurocholate and vinblastine on the Biliary Excretion of azelnidipine metabolites was also studied in control rats. Results: The Biliary Excretion of azelnidipine metabolites was delayed in EHBR. The Biliary Excretion of azelnidipine metabolites was inhibited by sulfobromophthalein and vinblastine, but was not inhibited by taurocholate or phenothiazine pretreatment. Conclusion: These findings suggest that the metabolites of azelnidipine are excreted into the bile partly by Mrp2 and P-glycoprotein.
Jack P Chism - One of the best experts on this subject based on the ideXlab platform.
-
correlation of Biliary Excretion in sandwich cultured rat hepatocytes and in vivo in rats
Drug Metabolism and Disposition, 1999Co-Authors: Jack P Chism, Edward L Lecluyse, Kenneth R Brouwer, Kim L. R. BrouwerAbstract:The relationship between Biliary Excretion in sandwich-cultured rat hepatocytes and in vivo in rats was examined. The Biliary Excretion of seven model substrates in 96-h sandwich-cultured rat hepatocytes was determined by differential cumulative uptake of substrate in the monolayers preincubated in standard buffer (intact bile canaliculi) and Ca2+-free buffer (disrupted bile canaliculi). Biliary Excretion in vivo was quantitated in bile duct-cannulated rats. The Biliary Excretion index of model substrates, equivalent to the percentage of retained substrate in the canalicular networks, was consistent with the percentage of the dose excreted in bile from in vivo experiments. The in vitro Biliary clearance of inulin, salicylate, methotrexate, [d-pen2,5]enkephalin, and taurocholate, calculated as the ratio of the amount excreted into the bile canalicular networks and the area under the incubation medium concentration-time profile (∼0, ∼0, 4.1 ± 1.0, 12.6 ± 2.2, and 56.2 ± 6.0 ml/min/kg, respectively), correlated with their intrinsic in vivo Biliary clearance (0.04, 0, 17.3, 34.4, and 116.9 ml/min/kg, respectively; r2 = 0.99). The model compound 264W94 was not excreted in bile either in vivo or in vitro. The glucuronide conjugate of 2169W94, theO-demethylated metabolite of 264W94, was excreted into bile in vitro when 2169W94, but not 264W94, was incubated with the monolayers; 2169W94 glucuronide undergoes extensive Biliary Excretion after administration of 264W94 or 2169W94 in vivo. Biliary Excretion in long-term sandwich-cultured rat hepatocytes correlates with in vivo Biliary Excretion. The study of Biliary Excretion of metabolites in the hepatocyte monolayers requires consideration of the status of metabolic activities.
