Enzymes hepatic drug metabolism, metabolite

The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radical intermediates) or initiate immune-mediated responses. With regard to the latter mechanism, serum from patients with halothane hepatitis contains a variety of autoantibodies against hepatic proteins, many of which are in a trifluoroacetylated form. These trifluoroacetylated proteins could be formed in the hepatocyte during the biotransformation of halothane by liver drug-metabolizing enzymes. However, TFA proteins have also been identified in the sera of patients who did not develop hepatitis after halothane anesthesia. 

Patients with hepatic insufficiency may not tolerate the drug at usual doses, however, because of increased area under the concentration curve of both parent drugs and metabolites. This may necessitate a dose reduction to 7.5 mg/kg every 12 hours or 5 mg/kg every 8 hours in some patients. Quinupristin and dalfopristin are not metabolized by cytochrome P450 enzymes but significantly inhibit CYP 3 A4, which metabolizes warfarin, diazepam, astemizole, terfenadine, cisapride, nonnucleo- side reverse transcriptase inhibitors, and cyclosporine, among others. Dosage reduction of cyclosporine may be necessary. 

K. L. R. Integration of hepatic drug transporters and phase II metabolizing enzymes Mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. Eur. J. Pharm. Sci. 27, 447-486, 2006. 

The test article is not metabolized by liver microsomes, or hepato-cytes This is indicated by the lack of either metabolite formation or parent disappearance in Studies 1 and 2. Hepatic metabolism is not involved in the metabolic clearance of the compound. There should be no concern with coadministered drugs that can alter drug-metabolizing enzyme activities. 

Kato Y, Haraguchi K, Kawashima M, et al. 1995. Induction of hepatic microsomal drug-metabolizing enzymes by methylsulphonyl metabolites of polychlorinated biphenyl congeners in rats. Chem Biol Interact 95 257-268. 

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