Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats

Bolder, U.; Trang, Nhan V.; Hagey, Lee R.; Schteingart, Claudio D.; Ton‐Nu, Huong‐Thu; Cerrè, Carolina; Elferink, Ronald P.J. Oude; Hofmann, Alan F.

doi:10.1016/s0016-5085(99)70356-2

Cited by 78 publications

(44 citation statements)

References 30 publications

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“…In cholestatic disease, most patients appear to conjugate their ingested UDCA completely based on analyses of biliary bile acids ( 316 ), but if conjugation were incomplete and unconjugated UDCA were secreted into bile, it would most likely be absorbed in the biliary ductules, thereby undergoing cholehepatic shunting. In further work from our laboratory, we showed that sulindac, but not other NSAIDs, also underwent cholehepatic shunting ( 317 ).…”

Section: Synthesis Of Labeled Bile Acids For Metabolic Studiesmentioning

confidence: 87%

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Hofmann

Hagey

2014

Journal of Lipid Research

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298

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conceptions are rare, and provocative judgments stand the test of time. Let us also hope that this effort will be both useful and entertaining. Each of the topics discussed merits at least a full length article, so there will be, of necessity in many instances, consideration of only what we perceive to be the highlights. THE EBB AND FLOW OF MEDICAL INTEREST IN BILE ACIDSAfter the elucidation of the true chemical structure of bile acids in 1932 (see below), there was little interest in bile acids in the Western world. One exception to this statement was the laboratory of Siegfried Thannhauser, who wrote the fi rst textbook of metabolic biochemistry in Germany. He studied cholesterol and bile acid balance in the biliary fi stula dog ( 1 ). During this time, bile acids were sold as liver tonics and laxatives, but there were no placebo-controlled studies showing effi cacy. Indeed, bile acids were considered by the medical profession to have no useful therapeutic properties. The tri-oxo derivative of cholic acid (called "dehydrocholic acid") was known to induce bile fl ow in animals ( 2 ), and was occasionally used to stimulate bile fl ow in patients; but again there were no controlled studies showing effi cacy in hepatobiliary disease.

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Section: Synthesis Of Labeled Bile Acids For Metabolic Studiesmentioning

confidence: 87%

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Hofmann

Hagey

2014

Journal of Lipid Research

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298

284

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“…37 In the mdr2 knockout mouse, whose phenotype is absent biliary phospholipid secretion, peribiliary fibrosis is diminished by norUDCA but not by UDCA. 38 Sulindac, a non-steroidal anti-inflammatory drug that also undergoes cholehepatic shunting in rats, 39 has been shown to improve plasma aminotransferase levels in primary biliary cirrhosis patients when used as an adjunct to UDCA. 40 Biotransformation patterns in humans may differ considerably from those in rodents, as shown by the current study as well as many others.…”

Section: Discussionmentioning

confidence: 99%

Novel biotransformation and physiological properties of norursodeoxycholic acid in humans

et al. 2005

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Experiments were performed in 2 volunteers to define the biotransformation and physiological properties of norursodeoxycholic acid (norUDCA), the C 23 (C 24 -nor) homolog of UDCA. To complement the in vivo studies, the biotransformation of norUDCA ex vivo using precision-cut human liver slices was also characterized. In the human studies, both a tracer dose given intravenously and a physiological dose (7.9 mmol, 3.0 g) given orally were excreted equally in bile and urine. By chromatography and mass spectrometry, the dominant biotransformation product of norUDCA in bile and urine was the C-23 ester glucuronide. Little N-acyl amidation (with glycine or taurine) occurred. The oral dose induced a sustained bicarbonate-rich hypercholeresis, with total bile flow averaging 20 L/kg/min, a rate extrapolating to 2 L/d. The increased bile flow was attributed to cholehepatic shunting of norUDCA as well to the lack of micelles in bile. Phospholipid and cholesterol secretion relative to bile acid secretion decreased during secretion of norUDCA and its metabolites, presumably also because of the absence of micelles in canalicular bile. When incubated with human liver slices, norUDCA was glucuronidated, whereas UDCA was conjugated with glycine or taurine. In conclusion, in humans, norUDCA is glucuronidated rather than amidated. In humans, but not animals, there is considerable renal elimination of the C-23 ester glucuronide, the dominant metabolite. NorUDCA ingestion induces a bicarbonaterich hypercholeresis and evokes less phospholipid and cholesterol secretion into bile than UDCA. Molecules that undergo cholehepatic shunting should be powerful choleretics in humans. (HEPATOLOGY 2005;42:1391-1398

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“…leukotriene B4) released by injured hepatocytes [24,33] , which in turn, can be damaged by TNF-a and IL-1b released from activated non-parenchymal cells. Examples of drug hepatotoxicity that involves non-parenchymal cells are that seen with methotrexate (activation of hepatic stellate cells to myofibroblasts, and liver fibrosis may develop even in the absence of liver enzyme elevation); bosentan (inhibition of transport proteins including the bile salt export pump [34] ); sulindac (competitive inhibition of canalicular bile salt transport, a contributing factor to cholestatic liver injury [35] ); cyclophosphamide and azathioprine (sinusoidal obstruction syndrome, venoocclusive disease, follows a severe depletion of GSH in sinusoidal endothelial cells. This damage results in fibrosis of the hepatic sinusoids).…”

Section: Targets Of Drug Hepatocellular Injurymentioning

confidence: 99%

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

Grattagliano

Bonfrate

Diogo

et al. 2009

WJG

123

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Drug-induced liver injury is a significant and still unresolved clinical problem. Limitations to knowledge about the mechanisms of toxicity render incomplete the detection of hepatotoxic potential during preclinical development. Several xenobiotics are lipophilic substances and their transformation into hydrophilic compounds by the cytochrome P-450 system results in production of toxic metabolites. Aging, preexisting liver disease, enzyme induction or inhibition, genetic variances, local O 2 supply and, above all, the intrinsic molecular properties of the drug may affect this process. Necrotic death follows antioxidant consumption and oxidation of intracellular proteins, which determine increased permeability of mitochondrial membranes, loss of potential, decreased ATP synthesis, inhibition of Ca 2+ -dependent ATPase, reduced capability to sequester Ca 2+ within mitochondria, and membrane bleb formation. Conversely, activation of nucleases and energetic participation of mitochondria are the main intracellular mechanisms that lead to apoptosis. Non-parenchymal hepatic cells are inducers of hepatocellular injury and targets for damage. Activation of the immune system promotes idiosyncratic reactions that result in hepatic necrosis or cholestasis, in which different HLA genotypes might play a major role. This review focuses on current knowledge of the mechanisms of drug-induced liver injury and recent advances on newly discovered mechanisms of liver damage. Future perspectives including new frontiers for research are discussed.

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Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats

Cited by 78 publications

References 30 publications

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Key discoveries in bile acid chemistry and biology and their clinical applications: history of the last eight decades

Novel biotransformation and physiological properties of norursodeoxycholic acid in humans

Biochemical mechanisms in drug-induced liver injury: Certainties and doubts

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