Question

Why do drugs undergo metabolism in the body? What are the organs in the body that are involved with drug metabolism? Explain in detail about Phase I and Phase II reactions

Answer 1

The purpose of metabolism in the body is usually to change the chemical structure of the substance,the increase the ease with which it can be excreted from the body.Drug metabolism is the chemical alteration of a drug by the body.Most drugs must pass through the liver,it is the primary site for metabolism.The liver's primary mechanism for metabolizing drugs is via a specific group of cytochrome P-450 enzymes.The level of these cytochrome P-450 enzymes controls the rate at which many drugs are metabolized.The capacity of the enzymes to metabolize is limited, so the can become overloaded when blood levels are high.The substances that result from metabolism may be inactive,or they may be similar to or different from the original drug in therapeutic activity or toxicity.Some drugs,called prodrugs ,are administered in an inactive form ,which is metabolized into active form.The resulting active metabolites produce the desired therapeutic effects.Metabolites may be metabolized further instead of being excreted from the body.The subsequent metabolites are then excreted.Excretion involves the elimination of drug from the body,for eg; the urine or bile.

Liver is the most important organ that involved in drug metabolism.In addition to the liver,every biological tissue of the body has the ability to metabolize the drugs.The other sites include lungs, kidney,placenta,epithelial cells of GI tract, adrenals and skin.

Phase 1 reaction is also known as non synthetic phase or non conjugative phase.It include the reactions which catalyze oxidation,reduction and hydrolysis of drugs.A change in drug molecule generally results in the introduction of a functional group into molecules or the exposure of new functional group of molecules.In phase 1 reactions ,small polar functional groups -OH,-NH₂,-SH,-COOH,etc.are either added or unmasked(if already present) on the lipid soluble drugs so that the resulting products may undergo phase 2 reactions.It results in activation,change or inactivation of drug.

Phase 2 reaction is also known as synthetic phase.It is the last step in detoxification reactions and almost always results in loss of biological activity of a compound.It may preceded by one or more of phase 1 reaction.It involves conjugation of functional groups of molecules with hydrophilic endogenous substrates.Formation of conjugates is formed with (an endogenous substance such as carbohydrates and amino acids) with drug or its metabolites formed in phase 1 reaction.Then attatchment of small polar endogenous molecules like glucuronic acid,sulphate,methyl ,amino acids,etc to either unchanged drug or to phase 1 products take place.Products called as 'conjugates' are water soluble metabolites which are readily excreted from the body.

Answer 2

Why Do Drugs Undergo Metabolism in the Body?

Drug metabolism is a biochemical process that modifies drugs to:

1. Enhance elimination (convert lipophilic drugs into water-soluble metabolites for excretion via urine/bile).

2. Detoxify harmful substances (reduce toxicity).

3. Activate prodrugs (convert inactive compounds into active forms).

4. Regulate drug duration (terminate pharmacological effects).

5. 
   

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Organs Involved in Drug Metabolism:

1. Liver (Primary Site):

• Contains high concentrations of metabolizing enzymes (e.g., cytochrome P450).

2. Intestines:

• Gut bacteria and enterocytes contribute to metabolism (e.g., hydrolysis).

3. Kidneys:

• Metabolize and excrete water-soluble metabolites.

4. Lungs/Skin:

• Minor roles in metabolizing inhaled or topical drugs.

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Phase I Reactions (Functionalization):

Goal: Introduce or expose polar groups (e.g., -OH, -COOH) to increase water solubility.
Key Reactions:

• Oxidation: Cytochrome P450 enzymes (e.g., hydroxylation, dealkylation).

• Reduction: Nitro-reductases (e.g., nitro-compounds → amines).

• Hydrolysis: Esterases/amidases (e.g., aspirin → salicylic acid).
  Example:

$$\text{Diazepam}\stackrel{\text{CYP450}}{\to }\text{Oxazepam (active metabolite)}$$

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Phase II Reactions (Conjugation):

Goal: Attach polar molecules to Phase I products to further enhance excretion.

Key Reactions:

• Glucuronidation: UGT enzymes (e.g., morphine → morphine-3-glucuronide).

• Sulfation: SULT enzymes (e.g., acetaminophen → sulfate conjugate).

• Acetylation/Methylation: NAT/COMT enzymes (e.g., isoniazid → acetyl-isoniazid).
  Example:

$$\text{Paracetamol}+\text{Glucuronic acid}\stackrel{\text{UGT}}{\to }\text{Paracetamol-glucuronide (excreted)}$$