How does drug metabolism impact the effects of drugs?

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Drugs are therapeutically significant chemicals and molecules. Drug metabolism is the enzymatic conversion of drugs to a new molecule inside the human body. It may produce an active, inactive, or toxic metabolite in this process. It can also be defined as biotransformation of therapeutically beneficial chemicals in one or more successive reactions. The reactions vary for different species of drugs.

Effects of Drugs

Metabolism mostly renders the drug inactive, yet certain metabolites are more active than the original drug. An active metabolite of a weak drug is called a prodrug. The metabolism rate of drugs increases with drug concentration.

Site of Action

In the process of drug metabolism, drugs undergo a chemical change initiated by the body. The liver is the principal site of this biotransformation, but there are other sites too that take part in the metabolism of specific drugs. The cytochrome P-450 enzyme system plays an active role in drug metabolism as they may be stimulated or inhibited by the various drugs, thus affecting the efficiency of the whole process. This, consequently, enhances or suppresses the activity of the drug. 

Cytochrome P-450 is a superfamily of isoenzymes. The electrons from NADPH–CYP450 reductase commences the oxidation of the drug compound by transferring electrons from NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) to CYP450. As defined by the name, “First-pass effect,” it describes that phenomenon where some drugs are metabolized by hepatic tissues immediately after absorption. Afterwards, the metabolites are released in the bile, thus leaving the less active drugs in the liver.

Drug Metabolism Reactions

Drug metabolism can take place through oxidation, hydrolysis, reduction, conjugation, or isomerization – all these biochemical reactions are intended to make the drug less toxic and easily excretable. The metabolism rates may vary – some drugs undergo rapid metabolism in some persons but it may be slow in other persons. Rapid metabolism will not allow the drug to reach the active therapeutic concentration in the body. Slow metabolism can render the drug toxic for the body. All these metabolic rates depend upon the genetic factors, and occurrence of any chronic liver disease or cardiovascular disorders because of which certain medicines can interfere in drug metabolism.

Phases in Drug Metabolism

Drug metabolism involves two phases, the occurrence of which may vary from compound to compound. Some drugs undergo only phase I or phase II reactions; phase numbers describe functional classification but not sequential classification.

1. Phase 1 transformations are non-synthetic reactions. They involve the reactions of functionalization. These reactions create a functional group or modify an existing one by certain reactions like hydrolysis, oxidation, or reduction.

2. Phase 2 transformations describe the reactions of conjugation, in which a drug or a metabolite couples with an endogenous conjugating molecule (e.g., sulphate, acetic acid, glycine) and these are synthetic reactions. Glucuronidation is the most common phase II reaction, followed by acetylation and sulfo conjugation. Sulphates are easily excreted out.

In drug metabolism, the metabolites are expected to be lower than the parent drug due to the addition of an ionizable group. This facilitates their faster excretion. However, there are certain exceptions which may lead to toxicity in blood due to drug metabolites. Specific monitoring of drugs to identify their therapeutic and toxic limits in a patient is very important.

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