Biotransformation of Drugs (Metabolism)

BIOTRANSFORMATION OF DRUGS (METABOLISM)

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Introduction

·       Biotransformation is the chemical alteration of drugs in the body, It is also called drug metabolism.

Purpose of Biotransformation

• To convert lipid-soluble drugs (which are hard to excrete) into water-soluble compounds (easily excretable via kidneys).
• To detoxify drugs and foreign substances (xenobiotics).
• To activate or deactivate drugs (e.g., prodrugs to active drugs).

Sites of Biotransformation

Organ	Role in Metabolism
Liver	Primary site – rich in enzymes
Kidneys	Secondary site
Lungs	Some volatile drugs
Plasma	Enzyme-mediated changes
Intestinal Mucosa	First-pass metabolism

Enzymes Involved in Biotransformation

• Cytochrome P450 enzyme system (CYP450) – Main group in the liver.
• Esterases, oxidases, reductases, hydrolases, etc.

Phases of Drug Metabolism

Phase I (Functionalization Reactions)

• Introduce or expose a polar group (–OH, –NH₂, –COOH)
• Makes the drug slightly more water-soluble
• Types:
• Oxidation (most common)
• Reduction
• Hydrolysis

Example: Diazepam → Oxazepam (via oxidation)

Phase II (Conjugation Reactions)

• Drug (or its metabolite from Phase I) is conjugated with a water-soluble substance
• Makes drug highly water-soluble and ready for excretion
• Types:
• Glucuronidation
• Sulfation
• Acetylation
• Methylation
• Glutathione conjugation

Example: Morphine → Morphine-glucuronide

Outcomes of Biotransformation

Effect	Example
Inactivation	Lidocaine → inactive metabolites
Activation of prodrugs	Enalapril → Enalaprilat
Decrease toxicity	Paracetamol overdose → hepatotoxic metabolite
No change	Some drugs are excreted unchanged

Factors Affecting Drug Biotransformation (Metabolism)

·       Drug biotransformation (metabolism) varies widely from person to person due to several influencing factors.

·       These factors can either increase, decrease, or alter the metabolic rate of a drug, which may affect its efficacy, toxicity, and duration of action.

 1. Age

• Neonates (newborns):
• Liver enzyme systems are immature.
• Reduced capacity for Phase I and Phase II reactions.
• Leads to slower metabolism → prolonged drug half-life → risk of toxicity.
• Example: Chloramphenicol can cause gray baby syndrome due to poor glucuronidation.
• Elderly:
• Liver size and hepatic blood flow decrease with age.
• Slower metabolism of many drugs.
• Increased sensitivity and risk of side effects.

 2. Genetic Factors (Pharmacogenetics)

• Genetic variations (polymorphisms) in metabolic enzymes affect how drugs are metabolized.
• Examples:
• CYP2D6 polymorphism:
• Poor metabolizers: Codeine may not convert to active morphine → poor pain relief.
• Ultra-rapid metabolizers: Increased morphine → risk of toxicity.
• NAT2 enzyme (acetylation):
• Slow acetylators: Higher risk of isoniazid-induced peripheral neuropathy.

 3. Enzyme Induction

• Some drugs, chemicals, or foods increase the activity of drug-metabolizing enzymes (especially CYP450).
• Result:
• Faster metabolism → decreased drug levels → reduced therapeutic effect.
• Examples of enzyme inducers:
• Rifampicin
• Phenytoin
• Carbamazepine
• Phenobarbital
• Smoking (induces CYP1A2)

4. Enzyme Inhibition

• Some substances inhibit the activity of drug-metabolizing enzymes.
• Result:
• Slower metabolism → increased drug levels → potential toxicity.
• Examples of enzyme inhibitors:
• Cimetidine
• Ketoconazole
• Erythromycin
• Grapefruit juice (inhibits CYP3A4)

5. Disease Conditions

• Liver Diseases:
• Conditions like hepatitis, cirrhosis, or liver cancer can reduce the number of functional hepatocytes and enzyme activity.
• Result: Decreased drug metabolism → accumulation of drug → toxicity.
• Renal Failure:
• Indirect effect: Accumulation of metabolites may inhibit hepatic enzymes.
• Cardiac failure or shock:
• Reduced hepatic blood flow → reduced drug delivery to liver → decreased metabolism.

6. Diet and Environmental Factors

• Certain foods and environmental substances can alter enzyme activity.

Substance	Effect	Example
Grapefruit juice	Enzyme inhibitor	Affects statins, leading to toxicity
Cruciferous vegetables (broccoli, cabbage)	Enzyme inducer	May reduce drug effect
Charcoal-grilled meat	Enzyme inducer	May affect metabolism of theophylline
Alcohol	Chronic use induces; acute use inhibits	Alters drug levels unpredictably
Pesticides and pollutants	Enzyme inducers	May reduce efficacy of medications

 7. Drug-Drug Interactions

• When two or more drugs are given together, they can affect each other’s metabolism:
• One drug may inhibit or induce the metabolism of another.
• Can lead to toxicity or therapeutic failure.
• Example:
• Warfarin + Metronidazole → increased bleeding risk (inhibition of warfarin metabolism).
• Oral contraceptives + Rifampicin → failure of contraception (enzyme induction).

8. Hormonal Status

• Hormones influence liver enzyme activity:
• Pregnancy: Increased estrogen/progesterone may alter metabolism.
• Hyperthyroidism: Increases metabolism.
• Hypothyroidism: Slows metabolism.

9. Route of Drug Administration

• Oral drugs undergo first-pass metabolism in the liver and intestine before reaching systemic circulation.
• This reduces the bioavailability of the drug.
• Parenteral routes (IV, IM) bypass first-pass metabolism.

Example: Propranolol has low oral bioavailability due to high first-pass effect.

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