Metabolism microsomal

It is important to remember that absolute oral bioavailability is a function of both absorption and first-pass metabolism. Therefore, a linear approach to predicting absolute oral bioavailability based on a single parameter, such as rate or extent of absorption (fraction of dose absorbed or estimated dose absorbed) or the rate of metabolism (microsomal or hepatic intrinsic clearance), may result in an inaccu-... 

Lipid-soluble xenobiotics are commonly biotra ns formed by oxidation in the drug-metabolizing microsomal system (DMMS). For each description below, choose the component of the microsomal mixed-function oxidase system with which it is most closely associated ... 

By Ames criteria, a chemical must be considered mutagenic if, at a dose of lOOy per plate, it more than doubles the number of spontaneous revertants, either with or without metabolizing microsomes. 

DMMS—drug-metabolizing microsomal system DNA—deoxyribonucleic acid dopa/DOPA/Dopa—(3,4-dlhydroxyphenylalanine)... 

This antihypertensive drug was withdrawn from use after a number of cases of occulomucocutaneous syndrome (skin rashes, keratinization of the eye, and other tissues). Mechanism is unknown, but there is evidence for metabolism (microsomal enzyme mediated) to a reactive intermediate capable of reacting with protein and forming antigenic conjugates. Antipractolol antibodies are detected in patients. Syndrome is not reproducible in animals, but in hamsters, practolol accumulates in the eye. 

Key Words environmental regulation of xenobiotic metabolism, microsomal enzyme induction, activation of microsomal enzymes, drug-drug interactions, diet-drug interactions... 

Low metabolic Microsome (hepatic, intestinal) or Reduce lipophilicity, block... 

Clark JM, Brooks MW (1989) Role of ion channels and intrateiminal calcium homeostasis in the action of deltamethrin at presynaptic nerve terminals. Biochem Pharmacol 38 2233-2245 Class TJ, Ando T, Casida JE (1990) Pyrethroid metabolism microsomal oxidase metabolites of (S)-bioallethrin and the six natural pyrethrins. J Agric Food Chem 38 529-537 Cole LM, Ruzo LO, Wood EJ, Casida JE (1982) Pyrethroid metabolism comparative fate in rats of tralomethrin, tralocythrin, deltamethrin, and (IR, alphaS)-cw-cypermethrin. J Agric Food Chem 30 631-636... 

The hver microsomal dmg-metabolizing system is of particular importance. This oxidative pathway is mediated by isozymes of the cytochrome family (Fig. 4). At least ten enzyme families exist to accommodate the abiUty of humans to handle many foreign molecules (21). 

The development of easy-to-use assays for determining theophylline blood levels afforded a handle on maintenance of effective but nontoxic levels. The relatively good availabihty of such assays in the United States probably contributed to the historical preference for theophylline treatment by U.S. physicians. Careful titration of the dose must be done on a patient-by-patient basis because individual rates of metaboHsm vary widely. Most ( 85%) of an oral dose of theophylline is metabolized by Hver microsomal enzymes. As a result many dmgs, eg, cimetidine [51481-61-9], anticonvulsants, or conditions, eg, fever, cigarette smoking, Hver disease, which affect Hver function alter theophylline blood levels. 

Pyrazolone-type dmgs, such as phenylbutazone and sulfinpyrazone, ate metabolized in the Hver by microsomal enzymes, forming glucutonide metabohtes that ate easily excreted because of enhanced water solubility. 

Ethanol also inhibits ADH-catalyzed retinol oxidation in vitro, and ethanol treatment of mouse embtyos has been demonstrated to reduce endogenous RA levels. The inhibition of cytosolic RolDH activity and stimulation of microsomal RolDH activity could explain ethanol-mediated vitamin A depletion, separate from ADH isoenzymes. Although the exact mechanism of inhibition of retinoid metabolism by ethanol is unclear, these observations are consistent with the finding that patients with alcoholic liver disease have depletedhepatic vitamin A reserves [review see [2]. 

Ethanol is oxidized by alcohol dehydrogenase (in the presence of nicotinamide adenine dinucleotide [NAD]) or the microsomal ethanol oxidizing system (MEOS) (in the presence of reduced nicotinamide adenine dinucleotide phosphate [NADPH]). Acetaldehyde, the first product in ethanol oxidation, is metabolized to acetic acid by aldehyde dehydrogenase in the presence of NAD. Acetic acid is broken down through the citric acid cycle to carbon dioxide (CO2) and water (H2O). Impairment of the metabolism of acetaldehyde to acetic acid is the major mechanism of action of disulfiram for the treatment of alcoholism. 

The microsomal ethanol oxidizing system is another mechanism of ethanol metabolism. CYP2E1 may be an important enzyme in the metabolism of ethanol in heavy drinkers, who may have a 10-fold increase in activity. Two aUehc variants in the gene cl and c2) are associated with differing enzymatic activity. Approximately 40% of Japanese have the more active c2 allele, which is rare in individuals of European heritage (Sun et al. 2002). It is not believed to be a risk or protective factor in the development of alcohohsm, although current studies are examining its relationship to a variety of ethanol-related diseases. 

Figure 5.54 Structures of Praziquantel and its metabolites, cis- and fraw5-4-hydroxy-praziquantel. Reprinted from 7. Chromatogr., B, 708, Lerch, C. and Blaschke, G., Investigation of the stereoselective metabolism of Praziquantel after incubation with rat liver microsomes by capillary electrophoresis and liquid chromatography-mass spectrometry , 267-275, Copyright (1998), with permission from Elsevier Science.

Compounds that affect activities of hepatic microsomal enzymes can antagonize the effects of methyl parathion, presumably by decreasing metabolism of methyl parathion to methyl paraoxon or enhancing degradation to relatively nontoxic metabolites. For example, pretreatment with phenobarbital protected rats from methyl parathion s cholinergic effects (Murphy 1980) and reduced inhibition of acetylcholinesterase activity in the rat brain (Tvede et al. 1989). Phenobarbital pretreatment prevented lethality from methyl parathion in mice compared to saline-pretreated controls (Sultatos 1987). Pretreatment of rats with two other pesticides, chlordecone or mirex, also reduced inhibition of brain acetylcholinesterase activity in rats dosed with methyl parathion (2.5 mg/kg intraperitoneally), while pretreatment with the herbicide linuron decreased acetylcholine brain levels below those found with methyl parathion treatment alone (Tvede et al. 1989). 

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