Acetaminophen drug metabolism studies

Another issue is drug metabolism and toxicity. Acetaminophen overdose remains a major cause of liver failure in the United States. Several P450s are involved in the oxidation to the reactive imi-noquinone . Studies with P450 2E1 knockout mice indicate that P450 2E1 is a major determinant of acetaminophen toxicity, because the toxicity was considerably attenuated in null animals ... 

Medication use must be monitored carefully for potential hepatotoxicity. Hepatically metabolized medications have the potential to accumulate in patients with liver disease. Little guidance is available on drug dosing in hepatic impairment because these patients are often excluded from drug trials. Daily acetaminophen use should not exceed 2 g. Dietary supplements have not been well studied in hepatic impairment and cannot be recommended. 

Other drugs are metabolised by Phase II synthetic reactions, catalysed typically by non-microsomal enzymes. Processes include acetylation, sulphation, glycine conjugation and methylation. Phase II reactions may be affected less frequently by ageing. Thus according to some studies, the elimination of isoniazid, rifampicin (rifampin), paracetamol (acetaminophen), valproic acid, salicylate, indomethacin, lorazepam, oxazepam, and temazepam is not altered with age. However, other studies have demonstrated a reduction in metabolism of lorazepam, paracetamol (acetaminophen), ketoprofen, naproxen, morphine, free valproic acid, and salicylate, indicating that the effect of age on conjugation reactions is variable. 

Much is known about the biochemical toxicology of hepatotoxicants, yet much remains to be learned. Hepatotoxicity resulting in either cell necrosis, fibrosis, or fatty infiltration is known to be a widespread phenomenon, potentially of importance to human health. It is caused by numerous drugs and environmental agents, and its incidence is expected to increase as confounding viral liver disease becomes more prevalent. Much is known about mechanisms based upon comprehensive studies with a few prototypical chemicals—namely, CCb, ethanol and acetaminophen—which support a convergence of varied primary effects on the ultimate failure of mitochondrial function and Ca2+ homeostasis. The extensive metabolic activity of the liver exposes its cells to a continuous flux of prooxidants. The importance of metabolic activation for the production of reactive metabolites is well-... 

B. Aniline Derivatives - A structure-activity study of a new series of alkoxyaniline derivatives has been reported along with a detailed workup of one of them . This compound (XII) appears to have good analgesic and anti-inflammatory activity, associated with some CNS depressant effects. An antidiuretic effect was described for acetaminophen 9 a d it was suggested that this drug might be a useful substitute for vasopressin in certain patients with diabetes insipidus. Evidence was also presented to show that acetophenetidin has antipyretic activity which is not dependent on metabolism to N-acetyl-p-aminophenol. 

Animal studies have indicated that evodia and compounds from evodia may affect the metabolism of theophylline, acetaminophen, chlorzoxazone, and caffeine (Bista et al. 2008 Jan et al. 2005 Lee et al. 2007 Tsai et al. 2005). In all of these studies, evodia or a compound from evodia was administered orally, while the drugs were administered intravenously. The relevance of those studies to human oral use is not known. 

For compounds metabolized through multiple pathways, which pathway leads to active (or reactive) metabolites in vivo For example, CPR/P450 of the cardiomyocyte was found not to be essential for the cardiotoxidty of doxorubicin, an anticancer drug, which can be metabolized by multiple enzymes, including CPR and carbonyl reductase, in a study that used a cardiomyocyte-specific Cpr-mW mouse (Fang et al., 2008). On the other hand, hepatic CPR/P450 enzymes were found to be essential for the hepatotoxicity and renal toxicity of acetaminophen, which can be metabolized by both phase I and phase II enzymes (Gu et al., 2005). 

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