Biotransformation hepatic drug metabolism

Interactions involving changes in the activity of hepatic drug-metabolizing enzyme systems have been discussed (see also Chapter 4 Drug Biotransformation and Appendix II). 

In the oral cavity, drug metabolism occurs in mucosal epithelial cells, microorganisms, and enzymes in the saliva metabolism also takes place in renal and hepatic tissue once the drug is swallowed. Although biotransformation of agents in the oral cavity is potentially an important aspect of reducing effective drug concentra-... 

Small molecules are eliminated from the body largely by means of drug metabolism enzymes in the liver and other tissues and by urinary excretion. Large molecules are also eliminated by renal and hepatic mechanisms. Proteins that are less than 40 to 50 kDa are cleared by renal filtration with little or no tubular reabsorption. Larger proteins are less likely to be filtered but may be subject to phagocytosis in hepa-tocytes and Kupfer cells in the liver. Protein biotransformation—denaturation, proteolysis, and oxidative metabolism—is also important. 

Most drug metabolism occurs in hepatic microsomes, although biotransformation also... 

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. 

Part of the family of hepatic microsomal drug metabolizing enzymes. Two isozymes (P450 2D6 and 3A4) responsible for biotransformation of 90% of drugs used clinically. 

The mechanism in hepatic cellular metabolism involves an electron transport system that functions for many drugs and chemical substances. These reactions include O-demethylation, N-demethyla-tion, hydroxylation, nitro reduction and other classical biotransformations. The electron transport system contains the heme protein, cytochrome P-450 that is reduced by NADPH via a flavoprotein, cytochrome P-450 reductase. For oxidative metabolic reactions, cytochrome P-450, in its reduced state (Fe 2), incorporates one atom of oxygen into the drug substrate and another into water. Many metabolic reductive reactions also utilize this system. In addition, there is a lipid component, phosphatidylcholine, which is associated with the electron transport and is an obligatory requirement for... 

Birkett DJ, Mackenzie PI, Veronese ME, Miners JO (1993) In vitro approaches can predict human drug metabolism. Trends Pharmacol Sci 14 292-294 Bloomer JC, Boyd HF, Hickey DMB et al. (2001) 1-(Arylpiperazinylamidoalkyl)-pyrimidones Orally Active Inhibitors of Lipoprotein-Associated Phospholipase A2. Bioorg Med Chem Lett 11 1925-1929 Brandon EFA, Raap CD, Meijerman I et al. (2003) An update on in vitro test methods in human hepatic drug biotransformation research pros and cons. Toxicol Applied Pharmacol 189 233-246... 

Numerous metabolic pathways involving mixed-fimction oxidases, esterases, transferases, and hydroxylases exhibit selectivity toward stereoisomeric substrates. Of all disposition differences that stereoisomers may display, the greatest stereoselectivity is expected in biotransformation, because of the specificity of metabolic enzymes and isoenzymes. The overall differences in hepatic clearance of stereoisomers reflect not only differences in intrinsic clearance (activity of drug metabolizing enzymes) for the isomers but also the steric effects of plasma protein binding and hepatic blood flow. 

All drugs administered to a patient are subject to biotransformation. Orally administered drugs are first subjected to metabolism by the intestinal epithelium and, upon absorption into the portal circulation, metabolized by the liver before entering the systemic circulation. While multiple tissues have certain degree of biotransformation capacity, it is generally accepted that hepatic metabolism represent the most important aspect of drug metabolism. 

---