Drug Metabolism

Metabolism, or biotransformation, is the critical chemical change a drug undergoes within the body. This process transforms the parent drug molecule into new molecular species, known as metabolites, using both enzymatic and non-enzymatic methods. This biological transformation is key to determining a drug's effectiveness, duration of action, and potential toxicity.

The Principal Sites and Outcomes of Metabolism

The liver is the primary site of drug metabolism, functioning as the body's main chemical processing plant. However, other organs also contribute significantly, including the kidney, gut, lungs, and plasma.

Drug metabolism can lead to three important outcomes:

Inactivation: Most drugs become pharmacologically inactive after metabolism (e.g., ibuprofen, paracetamol).
Formation of an Active Metabolite: The original drug is active, and its metabolite is also active (e.g., codeine is metabolized to morphine; primidone to phenobarbitone).
Inactive Drug Activation (Prodrugs): An initially inactive drug (prodrug) is metabolized into its active therapeutic form (e.g., levodopa is metabolized to dopamine; prednisone to prednisolone).

🧪 The Metabolic Enzymes: Microsomal vs. Non-microsomal

Drug metabolism relies on two broad categories of enzymes:

Enzyme Type	Location in Cell	Key Examples	Reactions Catalyzed
Microsomal Enzymes	Smooth endoplasmic reticulum of the liver, kidney, lungs, and intestinal mucosa.	Cytochrome P450 family, Monooxygenase, Glucuronyl Transferase.	Oxidative, reductive, hydrolytic, and glucuronidation processes.
Non-microsomal Enzymes	Cytoplasm and mitochondria of liver cells, and in plasma.	Flavoprotein oxidase, Amidase, Esterase, Conjugase.	All conjugations, several hydrolytic processes, and certain oxidation/reduction reactions.

The Cytochrome P450 (CYP450) system is the most important group of microsomal enzymes, responsible for metabolizing the vast majority of therapeutic drugs.

📈 Factors Affecting the Rate of Drug Metabolism

The rate at which a drug is metabolized is highly variable and is influenced by a complex interplay of internal and external factors.

1. Biological and Physiological Factors

Age: Metabolism varies significantly with age:

Neonates (up to 2 months) & Infants (2 months to 1 year): The microsomal enzyme system is underdeveloped, leading to slow metabolism. For example, Caffeine's half-life is about four days in neonates versus four hours in adults.
Children (1 to 12 years): They metabolize many drugs faster than adults (peaking between 6 and 12 years), often requiring a higher $\text{mg/kg}$ dosage.
Elderly: Decreased cardiac output, liver size, microsomal enzyme activity, and hepatic blood flow all contribute to decreased metabolism.

Sex Differences: Metabolic rates can vary after puberty due to sex hormones. Women tend to metabolize benzodiazepines more slowly than men.
Disease: Illnesses, particularly those affecting the liver, can drastically impair xenobiotic metabolism.
Hormones: Stress hormones, pregnancy, and other hormonal imbalances can impact metabolism.

2. Genetic and Species Factors

Genetic Factors: Variations between individuals or ethnic groups can lead to "fast" or "slow" metabolizers, resulting in excessive, extended, or toxic drug effects.
Species Differences: Significant qualitative and quantitative differences exist between species in both Phase I and Phase II reactions. For instance, human livers have less Cytochrome P450 per gram of tissue (10 to $20\ \text{nmol/g}$ ) compared to rat livers (30 to $50\ \text{nmol/g}$ ).

3. Environmental and Pharmacodynamic Factors

Diet:

Protein-rich diets enhance drug metabolizing capacity.
Fat-free diets can lower Cytochrome P-450 levels.
Grapefruit inhibits the metabolism of many drugs, increasing their oral bioavailability.
Deficiencies in certain vitamins and minerals slow enzyme metabolism.

Environmental Factors: Competition for metabolizing enzymes with other xenobiotics (foreign compounds) or drugs, or enzyme poisoning by toxic chemicals (like carbon monoxide), can drastically alter metabolism.
Pharmacodynamic Factors: The drug's dose, frequency, route of administration, and tissue distribution all influence its metabolic rate.

4. Stereochemical Factors

Stereochemical factors are crucial, as most drugs are chiral and often given as racemic mixtures (e.g., warfarin, ibuprofen). One enantiomer may interact preferentially with metabolizing enzymes, leading to different metabolic rates and pharmacological effects between the two forms. For example, the two enantiomers of $\alpha\text{-propoxyphene}$ have entirely different therapeutic activities: $(+)\text{-}\alpha\text{-propoxyphene}$ is an analgesic, while $(-)\text{-}\alpha\text{-propoxyphene}$ is an antitussive.