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Drug metabolism can result in Toxication or Detoxication - the activation or deactivation of the chemical. While both occur, the major metabolites of most drugs are detoxication products. Drugs are almost all Xenobiotic s. Other commonly used Organic Chemical s are also drugs, and are metabolized by the same Enzyme s as drugs. This provides the opportunity for '' Drug-drug '' and '' Drug-chemical '' Interactions or reactions. PHASE I VS. PHASE II Phase I and '''Phase II''' reactions are Biotransformation s of chemicals that occur during drug metabolism. ''Phase I reactions'' usually precede Phase II, though not necessarily. During these reactions, polar bodies are either introduced or unmasked, which results in (more) polar metabolites of the original chemicals. Phase I reactions may occur by Oxidation , Reduction or Hydrolysis reactions. If the metabolites of phase I reactions are sufficiently polar, they may be readily excreted at this point. However, many phase I products are not eliminated rapidly and undergo a subsequent reaction in which an endogenous substrate combines with the newly incorporated functional group to form a highly polar conjugate. ''Phase II reactions'' — usually known as conjugation reactions (e.g., with Glucuronic Acid , Sulfates , Glutathione or Amino Acids ) — are usually Detoxication in nature, and involve the interactions of the polar functional groups of phase I metabolites. SITES Quantitatively, the Liver is the principal organ of drug metabolism, although every Biological Tissue has some ability to metabolize drugs. Factors responsible for the liver's contribution to drug metabolism include that it is a large organ, that it is the first organ perfused by chemicals absorbed in the Gut , and that there are very high concentrations of most drug-metabolizing enzyme systems relative to other organs. If a drug is very readily and well-metabolized, it is said to show the '' First Pass Effect ''. Other sites of drug metabolism include Epithelial Cell s of the Gastrointestinal Tract , Lung s, Kidney s, and the Skin . These sites are usually responsible for localized toxicity reactions. MAJOR ENZYMES AND PATHWAYS Several major enzymes and pathways are involved in drug metabolism, and can be divided into Phase I and Phase II reactions: Phase I Oxidation
Reduction
It should be noted that during reduction reactions, a chemical can enter ''futile cycling'', in which it gains a free-radical electron, then promptly loses it to Oxygen (to form a Superoxide Anion ). Hydrolysis Phase II
FACTORS THAT AFFECT DRUG METABOLISM The duration and intensity of pharmacological action of most lipophilic drugs are determined by the rate they are metabolized to inactive products. The Cytochrome P450 Monooxygenase System is the most important pathway in this regard. In general, anything that ''increases'' the rate of metabolism (''e.g.'', Enzyme Induction ) of a pharmacologically active metabolite will ''decrease'' the duration and intensity of the drug action. The opposite is also true (''e.g.'', Enzyme Inhibition ). Various ''physiological'' and ''pathological'' factors can also affect drug metabolism. Physiological factors that can influence drug metabolism include age, individual variation (''e.g.'', Pharmacogenetics ), Enterohepatic Circulation , Nutrition , Intestinal Flora , or Sex Difference s. In general, drugs are metabolized more slowly in Fetal , Neonatal and Elderly Human s and Animal s than in Adult s. Genetic variation (polymorphism) accounts for some of the variability in the effect of drugs. With N-acetyltransferases (involved in ''Phase II'' reactions), individual variation creates a group of people who acetylate slowly (''slow acetylators'') and those who acetylate quickly, split roughly 50:50 in the population of Canada . This variation may have dramatic consequences, as the slow acetylators are more prone to dose-dependent toxicity. Cytochrome P450 Monooxygenase System enzymes can also vary across individuals, with deficiencies occurring in 1 - 30% of people, depending on their ethnic background. ''Pathological factors'' can also influence drug metabolism, including Liver , Kidney , or Heart diseases. REFERENCES
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