Ursodeoxycholate improves hepatobiliary dysfunction induced by valproate-carbamazepine treatment in the rat.

Carbamazepine (CBZ) and valproate (VPA) are commonly used antiepileptic drugs. These drugs, either alone or combined, may produce hepatotoxicity. We report results of a biochemical and histological study of the liver in rats treated for eight days with VPA (500 mg/Kg/day), CBZ (200 mg/Kg/day) and VPA plus CBZ. A hepatoprotective bile salt, ursodeoxycholate (UDC, 60 mg/Kg/day) was given as a supplement to rats treated with the VPA+CBZ combination. VPA strongly modified the biliary biochemical parameters inducing hypercholeresis and hyposecretion of phospholipids. Microscopically, hepatocytes showed intense vacuolation of the peripheral cytoplasm and alterations of the mitochondrial matrix. CBZ produced increased choleresis but had no effect on biliary lipid parameters. Ultrastructurally, CBZ induced marked proliferation of the smooth endoplasmic reticulum of hepatocytes. The VPA+CBZ association produced a combination of the alterations induced independently by each drug. In both bile and plasma, increased CBZ-epoxide and decreased VPA levels were observed. The addition of UDC restored the biliary phospholipid secretion, decreased cytoplasmic vacuoles and mitochondrial alterations, and diminished the hypertrophy of smooth endoplasmic reticulum, indicating a clear beneficial effect of UDC on hepatobiliary dysfunction induced by the VPA+CBZ combination. Furthermore, the supplementation with UDC did not significantly change the plasma levels of the antiepileptic drugs.

Ursodeoxycholate alleviates alcoholic fatty liver damage in rats.

The hydrophilic bile salt ursodeoxycholate (UDC) improves cholestasis in several liver diseases and is in vitro an efficient membrane stabilizer. However, its action on chronic ethanol-induced liver damage is not established. We thus sought to determine the effect of UDC on chronic ethanol-induced steatosis and on liver plasma membrane fluidity in rats. Male rats were pair-fed liquid diets containing 36% of calories as ethanol (alcohol diet) or an isocaloric maltose-dextrin mixture (control diet). Four groups of 10 animals received, respectively, during 30 days: the control diet, the control diet + UDC (90 mg/kg/day), the alcohol diet, and the alcohol diet + UDC. Bile was collected for assessment of bile flow, biliary lipids, and individual bile salts. Liver lipid contents and lipid peroxidation were determined. Plasma membrane fluidity was assessed by fluorescence polarization of various probes. Alcohol treatment caused a 4-fold increase in liver triacylglycerol and cholesterol ester levels. UDC supplementation significantly reduced these increases by 50% and 40%, respectively. UDC intake was associated with a marked decrease in alcohol-induced lipid peroxidation. Bile flow, bile salt, and phospholipid secretion were slightly increased by alcohol intake. The addition of UDC-enriched bile with tauroursodeoxycholate (38%) without significantly affecting the biliary parameters. Lastly, UDC treatment almost totally prevented the 20% increase in liver plasma membrane fluidity due to chronic alcohol intake. This study shows that UDC intake, concomitant with alcohol diet, exerts a clear-cut membrane protective effect that might alleviate ethanol-induced lipid disorders.

Contact solvents for common bile duct stones. Study in an in vitro system.

Cholesterol and brown pigment stones found in the common bile duct are often radiolucent and therefore indistinguishable. The purpose of this study was to define contact solvent systems able to dissolve both stone types. The influence of mucolytic agents on in vitro pigment stone dissolution was first determined. It was shown that dithioerythritol induced more rapid dissolution than N-acetylcysteine. Alternating treatment with an aqueous alkaline solvent (pH = 9.5), composed of sodium deoxycholate 50 mM, ethylenediaminetetraacetate 26 mM and dithioerythritol 50 mM, for 45 min, and an organic solvent methyl tert-butyl ether/dimethyl sulfoxide (90/10) for 15 min, was more effective for bilirubin, cholesterol, and fatty acid solubilization (p < 0.01) than using these solvents separately. The dissolution of brown stones was nearly completed within 9 h and that of mixed cholesterol stones was obtained within 3 h. We conclude that the alternating treatment described is very effective for the rapid in vitro dissolution of the two major stone types present in the bile ducts, and deserves further assessment in vivo.

Improvement of cyclosporin A-induced cholestasis by tauroursodeoxycholate in a long-term study in the rat.

Cyclosporin A is an essential immunosuppressive drug, but it is potentially toxic to the kidney and liver. Ursodeoxycholic acid, a hydrophilic bile acid, has been reported to improve cholestasis in liver disease in man. The purpose of this work was to examine whether tauroursodeoxycholate could reduce cyclosporin A-induced hepatic or renal injuries in the rat. After randomization into three groups (N = 8), rats received daily for 17 days: cyclosporin A intraperitoneally alone (30 mg/kg) or cyclosporin A intraperitoneally and tauroursodeoxycholate (60 mg/kg) by gavage; control received the cyclosporin A excipient. Under tauroursodeoxycholate, cholestatic parameters (bile flow, bile salt secretion, serum bile salts, serum bilirubin) improved significantly without affecting cyclosporin A blood levels, and excretion of the drug and its metabolites in bile increased by 47%. Serum creatinine levels were better preserved, although not significantly. These results show that tauroursodeoxycholate prevents cyclosporin A-induced cholestasis in long-term treatment in rats, possibly by facilitating the drug elimination in bile.