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Jurg Reichen - One of the best experts on this subject based on the ideXlab platform.
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the endothelin antagonist bosentan inhibits the canalicular bile salt export pump a potential mechanism for hepatic adverse reactions
Clinical Pharmacology & Therapeutics, 2001Co-Authors: Karin Fattinger, Christoph Funk, Michael Pantze, Cornelia Weber, Jurg ReichenAbstract:BACKGROUND: During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether Inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury. METHODS: We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro. RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P >.01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (Inhibition Constant, approximately 12 micromol/L) and metabolites (Inhibition Constant, approximately 8.5 micromol/L for metabolite Ro 47-8634). CONCLUSIONS: These results indicate that bosentan-induced liver injury is mediated, at least in part, by Inhibition of Bsep/BSEP-causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.
Karin Fattinger - One of the best experts on this subject based on the ideXlab platform.
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the endothelin antagonist bosentan inhibits the canalicular bile salt export pump a potential mechanism for hepatic adverse reactions
Clinical Pharmacology & Therapeutics, 2001Co-Authors: Karin Fattinger, Christoph Funk, Michael Pantze, Cornelia Weber, Jurg ReichenAbstract:BACKGROUND: During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether Inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury. METHODS: We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro. RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P >.01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (Inhibition Constant, approximately 12 micromol/L) and metabolites (Inhibition Constant, approximately 8.5 micromol/L for metabolite Ro 47-8634). CONCLUSIONS: These results indicate that bosentan-induced liver injury is mediated, at least in part, by Inhibition of Bsep/BSEP-causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.
Richard Thompson - One of the best experts on this subject based on the ideXlab platform.
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the human bile salt export pump characterization of substrate specificity and identification of inhibitors
Gastroenterology, 2002Co-Authors: J Byrne, Sandra Strautnieks, Giorgina Mieli Vergani, Christopher F Higgins, Kenneth J Linton, Richard ThompsonAbstract:Abstract Background & Aims: The bile salt export pump (BSEP) is the major bile salt transporter in the liver canalicular membrane. Our aim was to determine the affinity of the human BSEP for bile salts and identify inhibitors. Methods: Human BSEP was expressed in insect cells. Adenosine triphosphatase (ATPase) assays were performed, and bile salt transport studies were undertaken. Results: The BSEP gene, ABCB11 , was cloned and a recombinant baculovirus was generated. Infected insect cells expressed a 140-kilodalton protein that was absent in uninfected and in mock-infected cells. An ATPase assay showed BSEP to have a high basal ATPase activity. Transport assays were used to determine the Michaelis Constant for taurocholate as 4.25 μmol/L, with a maximum velocity of 200 pmol · min −1 · mg −1 protein. Inhibition Constant values for other bile salts were 11 μmol/L for glycocholate, 7 μmol/L for glycochenodeoxycholate, and 28 μmol/L for taurochenodeoxycholate. Cyclosporin A, rifampicin, and glibenclamide were proved to be competitive inhibitors of BSEP taurocholate transport, with Inhibition Constant values of 9.5 μmol/L, 31 μmol/L, and 27.5 μmol/L, respectively. Progesterone and tamoxifen did not inhibit BSEP. Conclusions: The human BSEP is a high-affinity bile salt transporter. The relative affinities for the major bile salts differ from those seen in rodents and reflect the different bile salt pools. BSEP is competitively inhibited by therapeutic drugs. This is a potentially significant mechanism for drug-induced cholestasis. GASTROENTEROLOGY 2002;123:1649-1658
Iwasaki Shigeo - One of the best experts on this subject based on the ideXlab platform.
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Interaction of Phomopsin a with porcine brain tubulin: Inhibition of tubulin polymerization and binding at a rhizoxin binding site
Biochemical pharmacology, 1992Co-Authors: Li Yin, Kobayashi Hlsayoshi, Tokiwa Yoshiyuki, Hashimoto Yuichi, Iwasaki ShigeoAbstract:Abstract Phomopsin A is an antimitotic cyclic peptide containing a 13-member ring including an ether linkage. It was isolated from the fungus Phomopsis leptostromiformis as the causal agent of lupinosis. Phomopsin A strongly inhibited microtubule assembly ( ic 50 : 2.4 μM). Our study using radiolabeled phomopsin A, prepared biosynthetically by feeding l -[U- 14 C]isoleucine to the culture of P. leptostromiformis , indicated that at least two binding sites of phomopsin A exist on tubulin on the basis of a Scatchard analysis; i.e. the dissociation Constants of a high affinity site ( K d 1 ) and a low affinity site ( K d 2 ) at 37° were determined to be 1 × 10 −8 and 3 × 10 −7 M, respectively. Phomopsin A inhibited the binding of radiolabeled rhizoxin to tubulin with an Inhibition Constant ( K i ) of 0.8 × 10 −8 M. This showed that the high affinity site of phomopsin A is identical to the rhizoxin binding site. The binding of the radiolabeled phomopsin A was also inhibited by rhizoxin and ansamitocin P-3, with an Inhibition Constant of 10 −7 M, and to a lesser extent by vinblastine. Phomopsin A had no inhibitory effect on colchicine binding to tubulin.
Cornelia Weber - One of the best experts on this subject based on the ideXlab platform.
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the endothelin antagonist bosentan inhibits the canalicular bile salt export pump a potential mechanism for hepatic adverse reactions
Clinical Pharmacology & Therapeutics, 2001Co-Authors: Karin Fattinger, Christoph Funk, Michael Pantze, Cornelia Weber, Jurg ReichenAbstract:BACKGROUND: During clinical trials bosentan, the first orally active endothelin receptor antagonist, caused asymptomatic transaminase elevations in some patients. In this study we investigated whether Inhibition of the hepatocanalicular bile salt export pump (rodents, Bsep; humans, BSEP ABCB11) could account for bosentan-induced liver injury. METHODS: We reanalyzed the safety database of the bosentan trials for cholestatic liver injury, determined the cholestatic potency of bosentan in the rat, and studied the effects of bosentan and its metabolites on Bsep-mediated taurocholate transport in vitro. RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P RESULTS: Bosentan caused dose-dependent and reversible liver injury in 2% to 18% of patients and caused a significant increase of serum bile salt levels (P >.01). Concomitant administration of glyburide (INN, glibenclamide) enhanced the cholestatic potency of bosentan. Similar effects were seen in rats, in which serum bile salt levels were increased by glyburide less than by bosentan, which increased the levels less than a combination of bosentan and glyburide. In vitro, Bsep-mediated taurocholate transport was inhibited by bosentan (Inhibition Constant, approximately 12 micromol/L) and metabolites (Inhibition Constant, approximately 8.5 micromol/L for metabolite Ro 47-8634). CONCLUSIONS: These results indicate that bosentan-induced liver injury is mediated, at least in part, by Inhibition of Bsep/BSEP-causing intracellular accumulation of cytotoxic bile salts and bile salt induced liver cell damage. The data further emphasize the pathophysiologic importance of drug-Bsep interactions in acquired forms of cholestatic liver injury.