Drug Metabolism (Biotransformation)

• Drug metabolism is the enzymatic conversion of drugs into metabolites for easier elimination, primarily occurring in the liver but also in the kidneys, lungs, intestines, and plasma.

Phases of Drug Metabolism

Phase I (Functionalization Reactions)

• These reactions introduce or expose a functional group (-OH, -NH2, -SH, -COOH) in the drug, making it more polar.

• These reactions mainly involve oxidation, reduction, and hydrolysis.

• The most important enzyme system in this phase is the Cytochrome P450 (CYP) enzyme system in the liver.

• Examples

  • Oxidation (CYP450) – Diazepam → Oxazepam

  • Reduction – Warfarin → Reduced Warfarin

  • Hydrolysis – Aspirin → Salicylic Acid

• May activate, inactivate, or form active metabolites (e.g., Codeine → Morphine).

Phase II (Conjugation Reactions)

• These reactions attach a large, polar molecule (e.g., glucuronic acid, sulfate, glycine) to the drug or Phase I metabolite, making it highly water-soluble for excretion.

• Phase II reactions mostly occur in the liver.

• Examples

  • Glucuronidation – Morphine → Morphine-6-glucuronide

  • Sulfation – Acetaminophen metabolism

  • Acetylation – Isoniazid metabolism

• Some drugs bypass Phase I and undergo direct Phase II metabolism (e.g., Morphine, Paracetamol).

Factors Affecting Drug Metabolism

• Age – Newborns & elderly have reduced metabolism.

• Genetics – Polymorphisms affect enzyme activity (e.g., slow/fast acetylators in isoniazid metabolism).

• Enzyme Induction/Inhibition:

  • Inducers (increase metabolism, ↓ drug effect) – Rifampin, Phenytoin, Carbamazepine.

  • Inhibitors (decrease metabolism, ↑ drug effect) – Ketoconazole, Erythromycin, Grapefruit juice.

• Liver Disease – Reduces metabolism (e.g., Cirrhosis slows drug clearance).

Drug Metabolizing Organs & Enzymes

Drug Metabolizing Organs

• Liver – Primary site, contains CYP, FMO, UGT, SULT, NAT enzymes.

• Kidneys – Minor metabolism in proximal tubules, mainly for excretion.

• Intestines – Metabolize oral drugs (first-pass effect).

• Lungs – Process inhaled & circulating drugs.

• Skin – Limited metabolism (esterases, CYP).

Drug Metabolizing Enzymes

1. CYP Enzymes – Major Phase I enzymes (oxidation). Key types: CYP3A4, CYP2D6, CYP2C9, CYP2C19, CYP1A2.

2. FMOs – Oxidize nitrogen, sulfur, phosphorus drugs.

3. Phase II Enzymes (Conjugation for excretion):

   • UGTs – Glucuronidation (e.g., morphine).

   • SULTs – Sulfation (e.g., acetaminophen).

   • NATs – Acetylation (e.g., isoniazid).

   • GSTs – Detox via glutathione.

   • Methyltransferases – Methylation alters drug polarity.

Metabolic Pathway

• A metabolic pathway is a sequence of biochemical reactions that convert a substrate into an end product through intermediates (metabolites).

Types of Metabolic Pathways

1) Anabolic Pathways (Biosynthesis)

• Build complex molecules from simple precursors, requiring ATP.

• Responsible for protein, lipid, carbohydrate, and nucleotide synthesis.

• Examples: Protein synthesis, fatty acid synthesis, nucleotide synthesis.

2) Catabolic Pathways (Degradation)

• Break down complex molecules, releasing ATP.

• Provide energy for cellular processes.

• Examples: Glycolysis, Krebs cycle, β-oxidation of fatty acids.