sulindac and Cholestasis

Nineteen-year-old woman with mixed connective tissue disease developed Stevens-Johnson syndrome following treatment of arthritis using sulindac. Involvements of infectious and malignant diseases have been ruled out and sulindac has strongly been suspected as a causative agent for Stevens-Johnson syndrome. Ten out of 13 cases with Stevens-Johnson syndrome associated with non-steroidal anti-inflammatory drugs, sulindac has been administrated. Four cases also presented with severe liver disease. Patients who developed Stevens-Johnson syndrome following sulindac administration did not have apparent common clinical or laboratory findings which might be implicated for development of this severe side effects. Among the various non-steroidal anti-inflammatory drugs, safety of sulindac has widely been appreciated. However, occurrence of severe adverse events as reported here indicated that sulindac should be administrated as carefully as other non-steroidal anti-inflammatory drugs.

Topics: Adult; Chemical and Drug Induced Liver Injury; Cholestasis; Female; Humans; Mixed Connective Tissue Disease; Stevens-Johnson Syndrome; Sulindac

Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

Topics: Administration, Oral; Animals; Chlorpromazine; Cholestasis; Cholesterol; Cyclosporine; Diclofenac; Dose-Response Relationship, Drug; Flutamide; Gene Expression; Humans; Imipramine; Inflammation; Ketoconazole; Liver; Methyltestosterone; Oxidative Stress; Rats; Risk Assessment; Sulindac; Tamoxifen; Toxicogenetics

Inhibition of the activity of the human bile salt export pump (BSEP: ABCB11) has been proposed to play a role in drug-induced liver injury (DILI). To enhance understanding of the relationship between BSEP inhibition and DILI, inhibition of human BSEP (hBSEP) and its rat ortholog (rBsep) by 85 pharmaceuticals was investigated in vitro. This was explored using assays that quantified inhibition of ATP-dependent [(3)H]taurocholate uptake into inverted plasma membrane vesicles from Sf21 insect cells, which expressed the proteins. Of the pharmaceuticals, 40 exhibited evidence of in vitro transporter inhibition and overall a close correlation was observed between potency values for inhibition of hBSEP and rBsep activity (r(2) = 0.94), although 12 drugs exhibited >2-fold more potent inhibition of hBSEP than rBsep. The median potency of hBSEP inhibition was higher among drugs that caused cholestatic/mixed DILI than among drugs that caused hepatocellular or no DILI, as was the incidence of hBSEP inhibition with IC(50) <300 μM. All drugs with hBSEP IC(50) <300 μM had molecular weight >250, ClogP >1.5, and nonpolar surface area >180Å. A clear distinction was not evident between hBSEP IC(50) or unbound plasma concentration (C(max, u)) of the drugs in humans and whether the drugs caused DILI. However, all 17 of the drugs with hBSEP IC(50) <100 μM and C(max, u) >0.002 μM caused DILI. Overall, these data indicate that inhibition of hBSEP/rBsep correlates with the propensity of numerous pharmaceuticals to cause cholestatic DILI in humans and is associated with several of their physicochemical properties.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; ATP-Binding Cassette Transporters; Bile Acids and Salts; Cell Line; Chemical and Drug Induced Liver Injury; Cholestasis; Drug-Related Side Effects and Adverse Reactions; Humans; Insecta; Rats; Risk Factors

Sulindac (SLD) is a nonsteroidal anti-inflammatory drug (NSAID) that has been associated with a greater incidence of idiosyncratic hepatotoxicity in human patients than other NSAIDs. One hypothesis regarding idiosyncratic adverse drug reactions is that interaction of a drug with a modest inflammatory episode precipitates liver injury. In this study, we tested the hypothesis that lipopolysaccharide (LPS) interacts with SLD to cause liver injury in rats. SLD (50 mg/kg) or its vehicle was administered to rats by gavage 15.5 h before LPS (8.3 x 10(5) endotoxin unit/kg) or its saline vehicle (i.v.). Thirty minutes after LPS treatment, SLD or vehicle administration was repeated. Rats were killed at various times after treatment, and serum, plasma, and liver samples were taken. Neither SLD nor LPS alone caused liver injury. Cotreatment with SLD/LPS led to increases in serum biomarkers of both hepatocellular injury and cholestasis. Histological evidence of liver damage was found only after SLD/LPS cotreatment. As a result of activation of hemostasis induced by SLD/LPS cotreatment, fibrin and hypoxia were present in liver tissue before the onset of hepatotoxicity. Heparin treatment reduced hepatic fibrin deposition and hypoxia and protected against liver injury induced by SLD/LPS cotreatment. These results indicate that cotreatment with nontoxic doses of LPS and SLD causes liver injury in rats, and this could serve as a model of human idiosyncratic liver injury. The hemostatic system is activated by SLD/LPS cotreatment and plays an important role in the development of SLD/LPS-induced liver injury.

Topics: Analysis of Variance; Animals; Chemical and Drug Induced Liver Injury; Cholestasis; Dose-Response Relationship, Drug; Fibrin; Hemostasis; Heparin; Hypoxia; Lipopolysaccharides; Liver; Male; Rats; Sulindac; Tumor Necrosis Factor-alpha

Topics: Acute Kidney Injury; Aged; Cholestasis; Female; Humans; Indenes; Nephritis, Interstitial; Sulindac

Topics: Aged; Cholestasis; Female; Humans; Indenes; Liver; Sulindac

Two patients who developed painless jaundice while taking sulindac are described. Rechallenge in one case confirmed the association of hepatic damage with sulindac administration. Laboratory data and liver biopsy findings suggested a hepatitis with cholestatic features.

Topics: Aged; Cholestasis; Female; Humans; Indenes; Jaundice; Liver; Sulindac

Topics: Bilirubin; Cholestasis; Female; Humans; Indenes; Liver; Middle Aged; Radiculopathy; Sulindac