Hepatic activation

Chick J, Lehert P, Landron F, et al Does acamprosate improve reduction of drinking as well as aiding abstinence J Psychopharmacol 17 397-A02, 2003 Chrostek L, Jelski W, Szmitkowski M, et al Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans. J Clin Lab Anal 17 93-96, 2003... 

Clopidogrel also inhibits the P2Yj2 ADP receptor following hepatic activation in... 

Continuous exposure to diets containing PCBs from Saginaw Bay carp induced cytochrome P-450 activity in a dose-dependent manner. Cytochrome P-450 activity in animals switched to the control diet from the PCB-containing diet was the same as controls. EROD hepatic activity is a potential biomarker for current exposure to PCBs and other similar cytochrome P-450 inducers... 

Collier, T.K. and U. Varanasi. 1991. Hepatic activities of xenobiotic metabolizing enzymes and biliary levels of xenobiotics in English sole (Parophrys vetulus) exposed to environmental contaminants. Arch. Environ. Contam. Toxicol. 20 462-473. 

Within a programme aimed at the development of thyroid hormone analogues as potentially useful plasma cholesterol-lowering agents, the pyrida-zinone derivative SK F L-94901 (98) has been prepared and investigated in the U.K. [419-422]. Whereas naturally occurring thyroid hormones cannot be employed for this purpose because of their undesirable effect on heart rate, (98) has been found to represent a potent thyromimetic which retains hepatic activity but lacks cardiac activity. Structural modifications and QSAR studies have been carried out [422]. 

An effect of ozone on lung microsomes has been suggested by morpholine studies that indicated alterations in the endoplasmic reticulum, Biochemical evidence of an effect on microsomal enzymes was originally obtained in the studies of Palmer et who demonstrated that ozone exposure (0.75-10 ppm for 3 h) resulted in a decrease in activity of Syrian hamster lung benzopyrene hydroxylase, a mixed-function oxidase that depends on cytochrome P-450. No changes in hepatic activities of this enzyme were observed, and the results were similar in animals in which high activities of benzopyrene hydroxylase had been induced. The maximal effect was not observed until a few days after the single ozone exposure. Palmer et also reported a decrease in rabbit tracheobronchial mucosal benzopyrene hydroxylase activity after exposure to similar ozone concentrations. 

The skin not only is a barrier to restrict diffusion of chemicals into the body, it is also an organ that can metabolize a variety of topically applied substances before they become systemically available. The skin has many of the same enzymes as the liver. The activities of several cutaneous enzymes in whole skin homogenates have been measured and compared to hepatic activity in the mouse. The activities of the enzymes in the whole skin homogenates were typically 2-6% of the hepatic values. However, there is evidence that the enzymes are present primarily in the epidermis. Because the epidermis makes up only 2-3% of the total skin, the real activities may range from 80% to 240% of those in the liver. Enzyme systems present include a qrtochrome P-450 system and a mixed-function oxidase system. 

Variable, weeks to months 2-10 days 26-107 days with chronic administration Hepatic, active metabolites... 

Hepatic activity. Hydrogenated oil, administered orally to male weanling rats at a dose... 

Bok, S.H., Lee, S.H., Park, Y.B., Bae, K.H., Son, K.H., Jeong, T.S., and Choi, M.S., Plasma and hepatic cholesterol and hepatic activities of 3-hydroxy-3-methyl-glutaryl-CoA reductase and acyl CoA cholesterol transferase are lower in rats fed citrus peel extract or a mixture of citrus bioflavonoids, J. Nutr., 129, 1182, 1999. 

EROD hepatic activity is a potential biomarker for current exposure to PCBs and other similar cytochrome P-450 inducers... 

Carbocyclic rings, unlike saturated heterocyclic rings, are not susceptible to the hepatic activation that is the basis of much drug toxicity. To pave the way for pharmaceutical discovery based on carbocyclic agents, much effort is going into the development of practical procedures for their stereocontrolled construction. 

A marked difference in hepatic activity of aldehyde oxidase between rats and monkeys was found to be responsible for the reported marked species difference in the metabolism of Zaleplon in vivo. In the postmito-chondrial fractions, S-9s, from liver homogenates of these animals, zaleplon was transformed in the presence of NADPH into the side chain oxidation product, N-desethyl-zaleplon, and the aromatic ring oxidation product, 5-oxo-zaleplon. In the rat S-9, N-desethyl-zaleplon and 5-oxo-zaleplon were a major and a very minor metabolites, respectively. 

Decrease blood urea nitrogen, a potential sign of altered hepatic activity, was also noted in... 

For patients with severe liver disease, captopril and lisinopril (i.e. not prodrugs, and not requiring hepatic activation and having almost solely renal elimination) are recommended. Enalaprilat (Fig. 6.18), the active metabolite of enalapril, is the only available ACE-inhibitor which is given intravenously, and can be used in patients with severe liver dysfunction. 

Ide, T. 2005. Interaction of fish oil and conjugated linoleic acid in affecting hepatic activity of lipogenic enzymes and gene expression in liver and adipose tissue. Diabetes, 54,412-423. 

Day 10 Sprague-Dawley rat embryos were exposed to benzene in culture for 2 days, then evaluated. Benzene at 3. 14 pmole/mL caused a significant decrease in yolk sac diameter and protein content of the embryo crown-rump length and somite number were decreased at both 1.56 and 3.14 pmole/mL benzene. A no-effect level of 0.82 pmole/mL was determined. In another study of cultured rat embryos, Chapman et al. (1994) evaluated the embryotoxic effects of benzene and several of its metabolites. Benzene at 1.6 mM produced little embryotoxicity, with or without hepatic activating enzymes, but phenol showed significant embryotoxicity in the presence of hepatic activation at concentrations as low as 0.01 mM. 

Adjacent tissue often shows local, non-specific reactive hepatitis (activation of Kupffer cells, small round-cellu-... 

Cyclophosphamide is a prodrug that requires cjdochrome P450 -dependent hepatic activation to produce alkylating species and several inactive by-products. However, very few metabolic interactions involving cyclophosphamide have been reported. In a retrospective study of 22 children treated with cyclophosphamide for cancer or bone marrow transplantation, cyclophosphamide clearance was significantly lower in nine patients taking fluconazole compared with 13 patients not taking it (77). In vitro studies in human hver microsomes confirmed that the rate of 4-hydroxylation of cyclophosphamide was inhibited by fluconazole. 

Elimination All macrolides are hepatically eliminated. Clarithromycin is hepatically activated to the 14-OH metabolite. Vk erythromycin < clarithromycin < azithromycin. 

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