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Metabolic changes of drugs and enzymes as drug targets

Metabolism plays a central role in the elimination of drugs and other foreign compounds (xenobiotics) from the body. A number oforganic compounds entering the body are relatively lipid-soluble (lipophilic). Once absorbed in the bloodstream, these molecules can diffuse passively through membranes to reach various target organs and effect their pharmacological action. If lipophilic drugs or xenobiotics were not metabolised to polar, water-soluble products that are readily excretable, they would remain indefinitely in the body, eliciting their biological effects. Thus, formation of water-soluble metabolites not only enhances drug elimination but also leads to compounds that are generally pharmacologically inactive and relatively nontoxic. For this reason, drug metabolism reactions have been traditionally regarded as detoxication (or detoxification) processes. However, it is not correct to assume that drug metabolism reactions always gave biologically inactive metabolites. Many drugs are biotransformed to pharmacologically active metabolites. Some metabolites have significant activity that contributes substantially to the pharmacological effect ascribed to the parent drug. In some cases, the parent compounds is inactive and must be converted to a biologicaly active metabolite. In addition, it is becoming increasingly clear that not all metabolites are nontoxic. Indeed many toxic side effect (e.g. tissue necrosis, carcinogenicity, teratogenicity) of drugs and environmental contamintants can be directly attributable to the formation of chemically reactive metabolites that are highly detrimental to the body. Drug metabolism reactions have been divided into two categories: phase I (functionalisation) and phase II (conjugation) reactions. Phase I includes oxidative, reductive, and hydrolytic biotransformations. The purpose of these reactions is to introduce a polar functional group (e.g. OH, COOH, NH2, SH) into the xenobiotic molecule. While phase I reactions may not produce sufficiently hydrophilic or inactive metabolites, they generally tend to provide a functional group or "handle" in the molecule that can undergo subsequent phase II reactions. The purpose of phase II reactions is to attach polar, and ionizable endogenous compounds such as glucuronic acid, sulfate, glycine, and other amino acids to the functional "handles" of phase I metabolites to form water-soluble conjugated products. Parent compounds that already have existing functional groups, such as OH, COOH, and NH2, are often directly conjugated by phase II enzymes. Conjugated metabolites are readily excreted in the urine and are generally devoid of pharmacological activity and toxicity. Thus, it is apparent that phase I and phase II reactions are complement one another in detoxifying and facilitating the elimination of drugs and xenobiotics. On the other hand, a great number of drugs depend on inhibition of a specific enzyme for their pharmacological activity. Examples of such drugs are used to treat cardiovasculas disease (ACE inhibitors), infectious disease (suicide antibiotics, trimethoprim in combined sulfonamides), and inflammatory disease (NSAID's). A number of different mechanisms exist by which an enzyme may be inhibited and they are reversible either competitive or noncompetitive and irreversible. The involvement of enzymes in disease makes them an obvious target for drugs. References 1. A. Parkinson, Biotransformation of xenobiotics, Chapter 6 in Casaret&Doull's Toxicology, The Basic Science of Poisons, 5th Ed., C. D. Klaassen (Ed.), McGraw-Hill, Inc. 1996, 114-186. 2. S. Rendić and F. J. Di Carlo, Human cytochrome P450 enzymes: A status report summarizing their reactions, substrates, inducers, and inhibitors, Drug Metab. Rev. 25, 1997, 413-580. 3. S. Rendić, The role and nature of metabolic reactions catalysed by enzymes citochrome P450 (CYP) in biological effects of medicines, Medicus 4/1, 1995, 49-65. 4. S. Rendić, Biotransformation of drugs by human cytochromes P450 (CYP): Toxic effects, activations, and drug-drug interactions, Medicus 2/3, 1995, 175-192. 5. I. Ahnfelt-Ronne, Enzymes and enzyme inhibitors, in Textbook of drug design and development, 2nd Ed. (P. Krogsgaard-Larsen et all. Ed.), Harwood Academic Publishers, Amsterdam, 1996, 289-326. 6. L. K. Low and N. Castagnoli, Jr., Metabolic changes of drugs and related organic compunds, in Wilson and Gisvold's textbook of organic medicinal and pharmaceutical chemistry, 8th Ed. (R. F. Doerge, Ed.), J. B. Lippincott Com., 1982, 55-127.

drug; enzyme; metabolism; biotransformation; drug development

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