Metabolism

In order to alter or stop a drug's biological activity and prepare it to be eliminated from the body, it must undergo one of the many different kinds of chemical transformations. One particularly important site for these actions is the liver. Metabolic reactions in the liver are catalyzed by enzymes located on a system of intracellular membranes known as the endoplasmic reticulum. In most cases, the resultant metabolites are less active than the parent drug. However, there are instances where the metabolite is as active as, or even more active than, the parent. In some cases, the toxic effects of drugs are produced by metabolites rather than the parent drug. Normally a drug undergoes a variety of biotransformation pathways, resulting in production of a mixture of intermediate metabolites. Rarely is only one metabolite produced from a single drug.

Some metabolites are inactive, i.e., their pharmacologically active parent compounds become inactivated or detoxicated. Certain metabolites retain the pharmacologic activity of their parent compounds to a greater or lesser extent. Fоr example, codeine is demethylated to the more active analgesic, morphine. Some metabolites develop activity different from that of their parent drug. Thus, vitamin A is isomerised to isotretinoic acid. Some pharmacologically inactive parent compounds are converted to active forms within the body. These parent compounds are known as prodrugs. The antiparkinsonian levodopa is decarboxylated in the neuron to active dopamine.

Many different kinds of reactions are catalyzed by drug–metabolizing enzymes, including oxidation, reduction, removal of substituent chemical groups, splitting of liable (chemically unstable) bonds, and addition of new substituents. The product is often less–lipid soluble than the parent, and is consequently excreted in the urine more rapidly.

Phase I reactions are those in which polar functional groups are introduced into the molecule or unmasked by oxidation, reduction, or hydrolysis. Oxidation is the most common phase I biotransformation. The majority of oxidation reactions occur in the liver, however, extrahepatic tissues, such as the intestinal mucosa, lungs and kidney, can also serve as metabolic sites. Reduction is less commonly encountered than oxidation; however, the result is the same – polar functional groups are formed, which can be eliminated in the urine. Enzymatic hydrolysis, the addition of water across a bond, also results in polar metabolites.

Phase II reactions are those in which the functional groups of the parent drug (or metabolite formed in phase I reaction) are masked by a conjugation reaction. Most phase II conjugates are very polar, and promote a rapid elimination of the drug from the body. Conjugation reactions combine the parent drug (or its metabolites) with certain natural endogenous constituents, such as glucoronic acid, glycine, glutamine, or other similar agents. There are six conjugation pathways: glucoronidation, sulfate conjugation, amino acid conjugation, glutathione conjugation, methylation and acetylation.

The factors that influence drug metabolism include the chemical structure of the drug, physiological state of the organism, the drug dosage, nutritional status of the patient, the age and gender of the patient, and the route of drug administration. In infants and young children, metabolizing enzyme systems are not fully developed, so they need smallerdoses of drugs than adults to avoid toxic side effects. This is particularly true for the drugs that require glucoronide conjugation. In the elderly, metabolizing enzyme systems decline. The lowered level of enzyme activity slows down the rate of drug elimination, causing higher plasma drug levels per dose than in young adults.

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1. Each parent drug produces one metabolite in the process of biotransformation.

2. The chief site of drug metabolism is the liver.

3. Enzymes in the liver promote excretion of metabolites in the urine by catalyzing the reactions.

4. There are three phases in metabolic reactions.

5. In elderly patients, the rate of drug elimination is increased, which lowers plasma drug levels per dose.

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II.10. Назовите основные этапы биотрансформации лекарства в организме.

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