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Walter Jäger - One of the best experts on this subject based on the ideXlab platform.
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Hepatic metabolism and biliary excretion of valerenic acid in isolated perfused rat livers role of mrp2 abcc2
Journal of Pharmaceutical Sciences, 2009Co-Authors: Alexandra Maiersalamon, Gabriele Trauner, Romy Hiltscher, Theresia Thalhammer, Gottfried Reznicek, Brigitte Kopp, Walter JägerAbstract:Abstract The study was designed to investigate the Hepatic metabolism and transport system of valerenic acid, a main active constituent of valerian, in isolated perfused livers from Wistar and Mrp2-deficient TR− rats. After administRation of 20 µM valerenic acid, the formation of seven valerenic acid glucuronides (M1–M7), namely two glucuronides of valerenic acid (M6, M7), four glucuronides of hydroxylated valerenic acid (M1, M3, M4, M5), and one glucuronide of hydroxylated dehydro-valerenic acid (M2) in bile and perfusate was quantified by HPLC. The Hepatic Extraction Ratio and clearance of valerenic acid were very high in Wistar and TR− rats (E: 0.983 ± 0.006 vs. 0.981 ± 0.004; Cl: 35.4 ± 0.21 mL/min vs. 35.3 ± 0.14 mL/min). However, biliary excretion and efflux of conjugates differed greatly in TR− rats. While cumulative biliary excretion of unconjugated valerenic acid and the glucuronides M1–M7 dropped dramatically to 1–9%, their efflux into perfusate increased 1.5- to 10-fold. This indicates that valerenic acid and its glucuronides are eliminated into bile by Mrp2. In summary, valerenic acid was metabolized to several conjugates, whereby the canalicular transporter Mrp2 mediated biliary excretion of the parent drug and its glucuronides. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3839–3849, 2009
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metabolism and disposition of resveratrol in the isolated perfused rat liver role of mrp2 in the biliary excretion of glucuronides
Journal of Pharmaceutical Sciences, 2008Co-Authors: Alexandra Maiersalamon, Theresia Thalhammer, Gottfried Reznicek, Birigt Hagenauer, Thomas Szekeres, Walter JägerAbstract:ABSTRACT In this study, the Hepatic metabolism and transport system for resveratrol was examined in isolated perfused livers from Wistar and Mrp2‐deficient TR − rats. Based on extensive metabolism to six glucuronides and sulfates (M1–M6), the Hepatic Extraction Ratio and clearance of resveratrol was very high in Wistar and TR − rats ( E : 0.998 vs. 0.999; Cl: 34.9 mL/min vs. 36.0 mL/min). However, biliary excretion and efflux of conjugates differs greatly in TR − rats. While cumulative biliary excretion of the glucuronides M1, M2, M3, and M5 dropped dramatically to 0–6%, their efflux into perfusate increased by 3.6‐, 1.8‐, 2.5‐, and 1.5‐fold. In contrast, biliary secretion of the sulfates M4 and M6 was partially maintained in the Mrp2‐deficient rats (61% and 39%) with a concomitant decline of their efflux into perfusate by 33.2% and 78.1%. This indicates that Mrp2 exclusively mediates the biliary excretion of resveratrol glucuronides but only partly that of sulfates. Cumulative secretion of unconjugated resveratrol into bile of TR − rats was only reduced by 40%, and into perfusate by 19%, suggesting only a minor role of Mrp2 in resveratrol elimination. In summary, resveratrol was dose‐dependently metabolized to several conjugates whereby the canalicular transporter Mrp2 selectively mediated the biliary excretion of glucuronides. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1615–1628, 2008
Alexandra Maiersalamon - One of the best experts on this subject based on the ideXlab platform.
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Hepatic metabolism and biliary excretion of valerenic acid in isolated perfused rat livers role of mrp2 abcc2
Journal of Pharmaceutical Sciences, 2009Co-Authors: Alexandra Maiersalamon, Gabriele Trauner, Romy Hiltscher, Theresia Thalhammer, Gottfried Reznicek, Brigitte Kopp, Walter JägerAbstract:Abstract The study was designed to investigate the Hepatic metabolism and transport system of valerenic acid, a main active constituent of valerian, in isolated perfused livers from Wistar and Mrp2-deficient TR− rats. After administRation of 20 µM valerenic acid, the formation of seven valerenic acid glucuronides (M1–M7), namely two glucuronides of valerenic acid (M6, M7), four glucuronides of hydroxylated valerenic acid (M1, M3, M4, M5), and one glucuronide of hydroxylated dehydro-valerenic acid (M2) in bile and perfusate was quantified by HPLC. The Hepatic Extraction Ratio and clearance of valerenic acid were very high in Wistar and TR− rats (E: 0.983 ± 0.006 vs. 0.981 ± 0.004; Cl: 35.4 ± 0.21 mL/min vs. 35.3 ± 0.14 mL/min). However, biliary excretion and efflux of conjugates differed greatly in TR− rats. While cumulative biliary excretion of unconjugated valerenic acid and the glucuronides M1–M7 dropped dramatically to 1–9%, their efflux into perfusate increased 1.5- to 10-fold. This indicates that valerenic acid and its glucuronides are eliminated into bile by Mrp2. In summary, valerenic acid was metabolized to several conjugates, whereby the canalicular transporter Mrp2 mediated biliary excretion of the parent drug and its glucuronides. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3839–3849, 2009
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metabolism and disposition of resveratrol in the isolated perfused rat liver role of mrp2 in the biliary excretion of glucuronides
Journal of Pharmaceutical Sciences, 2008Co-Authors: Alexandra Maiersalamon, Theresia Thalhammer, Gottfried Reznicek, Birigt Hagenauer, Thomas Szekeres, Walter JägerAbstract:ABSTRACT In this study, the Hepatic metabolism and transport system for resveratrol was examined in isolated perfused livers from Wistar and Mrp2‐deficient TR − rats. Based on extensive metabolism to six glucuronides and sulfates (M1–M6), the Hepatic Extraction Ratio and clearance of resveratrol was very high in Wistar and TR − rats ( E : 0.998 vs. 0.999; Cl: 34.9 mL/min vs. 36.0 mL/min). However, biliary excretion and efflux of conjugates differs greatly in TR − rats. While cumulative biliary excretion of the glucuronides M1, M2, M3, and M5 dropped dramatically to 0–6%, their efflux into perfusate increased by 3.6‐, 1.8‐, 2.5‐, and 1.5‐fold. In contrast, biliary secretion of the sulfates M4 and M6 was partially maintained in the Mrp2‐deficient rats (61% and 39%) with a concomitant decline of their efflux into perfusate by 33.2% and 78.1%. This indicates that Mrp2 exclusively mediates the biliary excretion of resveratrol glucuronides but only partly that of sulfates. Cumulative secretion of unconjugated resveratrol into bile of TR − rats was only reduced by 40%, and into perfusate by 19%, suggesting only a minor role of Mrp2 in resveratrol elimination. In summary, resveratrol was dose‐dependently metabolized to several conjugates whereby the canalicular transporter Mrp2 selectively mediated the biliary excretion of glucuronides. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1615–1628, 2008
Theresia Thalhammer - One of the best experts on this subject based on the ideXlab platform.
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Hepatic metabolism and biliary excretion of valerenic acid in isolated perfused rat livers role of mrp2 abcc2
Journal of Pharmaceutical Sciences, 2009Co-Authors: Alexandra Maiersalamon, Gabriele Trauner, Romy Hiltscher, Theresia Thalhammer, Gottfried Reznicek, Brigitte Kopp, Walter JägerAbstract:Abstract The study was designed to investigate the Hepatic metabolism and transport system of valerenic acid, a main active constituent of valerian, in isolated perfused livers from Wistar and Mrp2-deficient TR− rats. After administRation of 20 µM valerenic acid, the formation of seven valerenic acid glucuronides (M1–M7), namely two glucuronides of valerenic acid (M6, M7), four glucuronides of hydroxylated valerenic acid (M1, M3, M4, M5), and one glucuronide of hydroxylated dehydro-valerenic acid (M2) in bile and perfusate was quantified by HPLC. The Hepatic Extraction Ratio and clearance of valerenic acid were very high in Wistar and TR− rats (E: 0.983 ± 0.006 vs. 0.981 ± 0.004; Cl: 35.4 ± 0.21 mL/min vs. 35.3 ± 0.14 mL/min). However, biliary excretion and efflux of conjugates differed greatly in TR− rats. While cumulative biliary excretion of unconjugated valerenic acid and the glucuronides M1–M7 dropped dramatically to 1–9%, their efflux into perfusate increased 1.5- to 10-fold. This indicates that valerenic acid and its glucuronides are eliminated into bile by Mrp2. In summary, valerenic acid was metabolized to several conjugates, whereby the canalicular transporter Mrp2 mediated biliary excretion of the parent drug and its glucuronides. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3839–3849, 2009
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metabolism and disposition of resveratrol in the isolated perfused rat liver role of mrp2 in the biliary excretion of glucuronides
Journal of Pharmaceutical Sciences, 2008Co-Authors: Alexandra Maiersalamon, Theresia Thalhammer, Gottfried Reznicek, Birigt Hagenauer, Thomas Szekeres, Walter JägerAbstract:ABSTRACT In this study, the Hepatic metabolism and transport system for resveratrol was examined in isolated perfused livers from Wistar and Mrp2‐deficient TR − rats. Based on extensive metabolism to six glucuronides and sulfates (M1–M6), the Hepatic Extraction Ratio and clearance of resveratrol was very high in Wistar and TR − rats ( E : 0.998 vs. 0.999; Cl: 34.9 mL/min vs. 36.0 mL/min). However, biliary excretion and efflux of conjugates differs greatly in TR − rats. While cumulative biliary excretion of the glucuronides M1, M2, M3, and M5 dropped dramatically to 0–6%, their efflux into perfusate increased by 3.6‐, 1.8‐, 2.5‐, and 1.5‐fold. In contrast, biliary secretion of the sulfates M4 and M6 was partially maintained in the Mrp2‐deficient rats (61% and 39%) with a concomitant decline of their efflux into perfusate by 33.2% and 78.1%. This indicates that Mrp2 exclusively mediates the biliary excretion of resveratrol glucuronides but only partly that of sulfates. Cumulative secretion of unconjugated resveratrol into bile of TR − rats was only reduced by 40%, and into perfusate by 19%, suggesting only a minor role of Mrp2 in resveratrol elimination. In summary, resveratrol was dose‐dependently metabolized to several conjugates whereby the canalicular transporter Mrp2 selectively mediated the biliary excretion of glucuronides. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1615–1628, 2008
Gottfried Reznicek - One of the best experts on this subject based on the ideXlab platform.
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Hepatic metabolism and biliary excretion of valerenic acid in isolated perfused rat livers role of mrp2 abcc2
Journal of Pharmaceutical Sciences, 2009Co-Authors: Alexandra Maiersalamon, Gabriele Trauner, Romy Hiltscher, Theresia Thalhammer, Gottfried Reznicek, Brigitte Kopp, Walter JägerAbstract:Abstract The study was designed to investigate the Hepatic metabolism and transport system of valerenic acid, a main active constituent of valerian, in isolated perfused livers from Wistar and Mrp2-deficient TR− rats. After administRation of 20 µM valerenic acid, the formation of seven valerenic acid glucuronides (M1–M7), namely two glucuronides of valerenic acid (M6, M7), four glucuronides of hydroxylated valerenic acid (M1, M3, M4, M5), and one glucuronide of hydroxylated dehydro-valerenic acid (M2) in bile and perfusate was quantified by HPLC. The Hepatic Extraction Ratio and clearance of valerenic acid were very high in Wistar and TR− rats (E: 0.983 ± 0.006 vs. 0.981 ± 0.004; Cl: 35.4 ± 0.21 mL/min vs. 35.3 ± 0.14 mL/min). However, biliary excretion and efflux of conjugates differed greatly in TR− rats. While cumulative biliary excretion of unconjugated valerenic acid and the glucuronides M1–M7 dropped dramatically to 1–9%, their efflux into perfusate increased 1.5- to 10-fold. This indicates that valerenic acid and its glucuronides are eliminated into bile by Mrp2. In summary, valerenic acid was metabolized to several conjugates, whereby the canalicular transporter Mrp2 mediated biliary excretion of the parent drug and its glucuronides. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:3839–3849, 2009
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metabolism and disposition of resveratrol in the isolated perfused rat liver role of mrp2 in the biliary excretion of glucuronides
Journal of Pharmaceutical Sciences, 2008Co-Authors: Alexandra Maiersalamon, Theresia Thalhammer, Gottfried Reznicek, Birigt Hagenauer, Thomas Szekeres, Walter JägerAbstract:ABSTRACT In this study, the Hepatic metabolism and transport system for resveratrol was examined in isolated perfused livers from Wistar and Mrp2‐deficient TR − rats. Based on extensive metabolism to six glucuronides and sulfates (M1–M6), the Hepatic Extraction Ratio and clearance of resveratrol was very high in Wistar and TR − rats ( E : 0.998 vs. 0.999; Cl: 34.9 mL/min vs. 36.0 mL/min). However, biliary excretion and efflux of conjugates differs greatly in TR − rats. While cumulative biliary excretion of the glucuronides M1, M2, M3, and M5 dropped dramatically to 0–6%, their efflux into perfusate increased by 3.6‐, 1.8‐, 2.5‐, and 1.5‐fold. In contrast, biliary secretion of the sulfates M4 and M6 was partially maintained in the Mrp2‐deficient rats (61% and 39%) with a concomitant decline of their efflux into perfusate by 33.2% and 78.1%. This indicates that Mrp2 exclusively mediates the biliary excretion of resveratrol glucuronides but only partly that of sulfates. Cumulative secretion of unconjugated resveratrol into bile of TR − rats was only reduced by 40%, and into perfusate by 19%, suggesting only a minor role of Mrp2 in resveratrol elimination. In summary, resveratrol was dose‐dependently metabolized to several conjugates whereby the canalicular transporter Mrp2 selectively mediated the biliary excretion of glucuronides. © 2007 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:1615–1628, 2008
Reza Mehvar - One of the best experts on this subject based on the ideXlab platform.
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Application of Organ Clearance to Estimation of the In Vivo Hepatic Extraction Ratio.
Current clinical pharmacology, 2016Co-Authors: Reza MehvarAbstract:Organ clearance, which has been derived from the organ blood flow and Extraction Ratio (E), has been extensively used by clinical pharmacologists to explain the pharmacokinetics of many drugs in health and disease. For example, the extent of Hepatic clearance or E (Eh) of drugs would determine their response to changes in the liver blood flow and/or activities of the metabolizing enzymes. Although Eh may be obtained directly by cannulating internal blood vessels, the method is invasive. Therefore, indirect methods have been used to estimate Eh from the peripheral blood concentRation-time data after intravascular administRation of drugs. Additionally, these indirect methods require an estimate of the liver blood flow in the patients or animals. However, some investigators use plasma concentRations and/or liver plasma flow for the estimation of Eh, which could potentially result in significant errors. It is shown here that when plasma concentRations are used along with liver blood flow, an overestimation or underestimation of the true value will result if the blood: plasma concentRation (B:P) Ratio is >1 or < 1, respectively, with the estimated Eh being different from the true value by a factor equal to the B:P Ratio. On the other hand, the use of plasma concentRations and plasma liver flow will always result in an overestimation of the true Eh unless the drug does not penetrate the red blood cells. It is concluded that for the accurate estimation of Eh from the in vivo data, the blood concentRation and blood flow should be used.
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effects of in vivo Hepatic ischemia reperfusion injury on the hepatobiliary disposition of rhodamine 123 and its metabolites in isolated perfused rat livers
Journal of Pharmacy and Pharmaceutical Sciences, 2012Co-Authors: Ridhi Parasrampuria, Imam H Shaik, Reza MehvarAbstract:Purpose. A few studies have shown that normothermic Hepatic ischemia-reperfusion (IR) injury may affect the mRNA and/or protein levels of canalicular transporters P-glycoprotein (P-gp) and multidrug resistance-associated protein 2 (Mrp2). However, the effects of the injury on the functions of these canalicular transporters with respect to the biliary excretion of drugs remain largely unknown. Therefore, the purpose of this study was to investigate the effects of warm Hepatic IR on the hepatobiliary disposition of rhodamine 123 (RH-123), a P-gp substrate, and its glucuronidated metabolite (RH-Glu), an Mrp2 substrate, in rats. Methods. Twenty four or 72 h following a 60-min partial ischemia or sham opeRation in rats, livers were isolated and perfused ex vivo with a constant concentRation (~100 ng/mL) of RH-123. The concentRation of RH-123 and its glucuronidated (RH-Glu) and deacylated (RH-110) metabolites were determined in the outlet perfusate, bile, and the liver tissue using HPLC, and relevant pharmacokinetic parameters were estimated. Results. Twenty-four-h IR caused a significant reduction in the Hepatic Extraction Ratio of RH-123 (IR: 0.857 ± 0.078; Sham: 0.980 ± 0.017) and the biliary recovery of the parent drug and RH-Glu by 43% and 44%, respectively. The reductions in the biliary recovery were associated with significant reductions in the apparent biliary clearance of RH-123 and RH-Glu. Mass balance data showed that the formation of the glucuronidated or deacylated metabolite was not significantly affected by the 24-h IR injury. In contrast to the 24-h IR, the injury did not have any effect on the hepatobiliary disposition of RH-123 or its metabolites following 72 h of reperfusion. Conclusions. It is concluded that the pharmacokinetics of drugs that are subject to biliary excretion by the canalicular P-gp and Mrp2 transporters may be altered shortly after Hepatic IR injury. This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.