thiobenzamide and Chemical-and-Drug-Induced-Liver-Injury

A substituted aryl amide derivative of 6-naltrexamine--17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4'-trimethylfluoro)benzamido]morphinan-hydrochloride--(compound 5), previously shown to be a potent κ-opioid receptor antagonist, was used to characterize the physicochemical properties and efficacy to decrease alcohol self-administration in alcohol-preferring rats (P-rats) and binge-like P-rats. Previous studies showed that compounds closely related to compound 5 possessed favorable properties regarding penetration of the blood-brain barrier. Pharmacokinetic studies showed that compound 5 had acceptable bioavailability. In contrast to other κ-receptor antagonists, in particular norbinaltorphimine, compound 5 showed favorable drug-like properties. Based on these findings, further studies were done. Safety studies showed that compound 5 was not hepatotoxic at doses 200-fold greater than an efficacious dose. The effects of compound 5 or naltrexone on the hepatotoxicity of thiobenzamide were investigated. In contrast to naltrexone, which exacerbated thiobenzamide-mediated hepatotoxicity, compound 5 was observed to be hepatoprotective. Based on the physicochemical properties of compound 5, the compound was examined in rat animal models of alcohol self-administration. The inhibition of ethanol self-administration by compound 5 in alcohol-dependent and alcohol-nondependent P-rats trained to self-administer a 10% (w/v) ethanol solution, using operant techniques, showed very potent efficacy (i.e., estimated ED50 values of 4-5 μg/kg). In a binge-like P-rat animal model, inhibition of alcohol self-administration by compound 5 had an estimated ED50 value of 8 μg/kg. The results suggest that compound 5 is a potent drug-like κ-opioid receptor antagonist of utility in alcohol cessation medications development.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Conditioning, Operant; Ethanol; Male; Morphinans; Naltrexone; Narcotic Antagonists; Rats; Rats, Inbred Strains; Self Administration; Thioamides

Differences in the nature and extent of hepatic injury were examined after administration of para-substituted thiobenzamides to rats. In accordance with previous studies, the extent of hepatotoxicity varied with the electron-donating ability of the substituent. There was also a good correlation between the extent of hepatic necrosis and the amount of substituted thiobenzamide sulfoxide found in the plasma after intraperitoneal dosing. The nature of the hepatic lesion, characterized as a combination of hepatic necrosis, ballooning degeneration, and biliary dysfunction, varied qualitatively with each thiobenzamide analog. When the hepatotoxicity of thiobenzamide was compared after either intraperitoneal or oral dosing, differences in the extent of hepatic necrosis, ballooning degeneration, transaminase elevation, and biliary dysfunction were observed. Intraperitoneal dosing with thiobenzamide gave less severe necrosis and more pronounced elevations in bile acids, while oral dosing led to more severe necrosis along with impaired biliary function. The route of administration was shown to dramatically affect the pharmacokinetics of thiobenzamide and thiobenzamide sulfoxide. Intraperitoneal administration of thiobenzamide gave high plasma and liver levels of both thiobenzamide and thiobenzamide sulfoxide, whereas oral administration gave slightly lower levels of the sulfoxide but much lower levels of thiobenzamide. The reason for greater hepatic necrosis after oral administration may be due to a greater ability to further metabolize the sulfoxide to a reactive metabolite in the absence of high levels of thiobenzamide.

Topics: Administration, Oral; Alanine Transaminase; Animals; Aspartate Aminotransferases; Bile Acids and Salts; Bilirubin; Chemical and Drug Induced Liver Injury; Female; Injections, Intraperitoneal; Liver; Liver Diseases; Male; Microsomes, Liver; Necrosis; Rats; Rats, Inbred Strains; Thioamides; Transaminases

The effect of acetone pretreatment (5% in drinking water for 10 days on rat liver metabolism and toxicity of thiobenzamide (TB) was investigated. Hepatic microsomes from acetone-pretreated rats showed a significant increase of TB-S-oxidation rate which, on the basis of selective thermal inactivation of FAD-containing monooxygenase (FADM), appeared dependent only on cytochrome P-450. Furthermore, TB was able to competitively inhibit acetone hydroxylase (AcH), an enzymatic reaction highly specific for the P-450IIE1 isozyme. Acetone pretreatment of rats also produced an exacerbation of liver damage induced by acute administration of TB (150 mg/kg), as judged by the extent of liver necrosis and serum alanine-amino transferase (ALAT) activities. Coadministration of acetone with TB reduced on the other hand the extent of liver damage. The findings suggest that P-450 species induced by acetone, and in particular the P-450IIE1 isozyme, could be involved in the biotransformation of TB.

Topics: Acetone; Alanine Transaminase; Amides; Animals; Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme System; Enzyme Induction; In Vitro Techniques; Isoenzymes; Kinetics; Male; Microsomes, Liver; Oxidation-Reduction; Rats; Rats, Inbred Strains; Thioamides

Topics: Amides; Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Male; Rats; Rats, Inbred Strains; Thioamides

Topics: Alanine Transaminase; Amides; Animals; Antitubercular Agents; Chemical and Drug Induced Liver Injury; Electrons; Male; Models, Biological; Rats; Rats, Inbred Strains; Thioamides

Topics: Alanine Transaminase; Animals; Benzamides; Bilirubin; Chemical and Drug Induced Liver Injury; Dose-Response Relationship, Drug; Male; Phenobarbital; Proadifen; Rats; Structure-Activity Relationship; Thioamides; Thiones; Triglycerides