L4


I. Definition and Basics of Drug Metabolism

  • Definition (Core Concept 14): The chemical transformation of a drug into one or more products (metabolites) within the body.

  • Scope:

    • Metabolism is not universal: Some drugs, particularly hydrophilic ones like penicillin or lithium, remain intact and are excreted as they were absorbed.

    • First-pass Metabolism: Orally administered drugs often undergo significant metabolism in the gut wall and the liver before reaching systemic circulation.

    • Effect on Bioavailability: Extensive first-pass metabolism decreases the bioavailability and absorption of a drug.

  • Biological Purpose: Metabolism generally increases the molecular size and hydrophilicity of substances, facilitating renal or hepatobiliary excretion and preventing tissue accumulation.

II. Enzyme Locations and Phase Reactions

Drug metabolism is primarily mediated by enzymes located in several cellular compartments, mostly within hepatocytes (liver cells):

  • Endoplasmic Reticulum (ER) Membranes: Site of Cytochrome P450 (CYP) enzymes.

  • Cytosol: Contains enzymes like alcohol dehydrogenase.

  • Mitochondria: Contains enzymes like aldehyde dehydrogenase.

Phase 1 Metabolism (Functionalisation)

This phase generates or attaches a functional group to the parent drug.

  1. Oxidation: Adding an oxygen atom or removing a hydrogen atom (e.g., Ethanol →\rightarrow Acetaldehyde via alcohol dehydrogenase).

  2. Dealkylation: Removal of alkyl groups, such as demethylation. (e.g., Codeine →\rightarrow Morphine via CYP2D6).

  3. Hydrolysis: Breaking ester or amide bonds. This is crucial for pro-drugs—inactive molecules designed to improve oral delivery that become active once metabolised in vivo (e.g., Tenofovir alafenamide →\rightarrow Tenofovir).

Phase 2 Metabolism (Coupling)

This phase involves attaching a polar endogenous molecule to a functional group to increase water solubility.

  1. Glucuronidation: The most common reaction. UGT (UDP glucuronosyltransferase) transfers glucuronic acid to a drug (e.g., Morphine →\rightarrow Morphine-3-glucuronide).

  2. Sulfation: SULT (sulfotransferase) transfers a sulfonate group from PAPS.

  3. Glutathione Conjugation: GST (glutathione-S-transferase) attaches glutathione. This is a critical detoxification pathway for reactive metabolites like NAPQI (from paracetamol).

III. Outcomes of Drug Metabolism

Metabolism can alter biological activity, terminate action, or create toxic byproducts:

  • Active →\rightarrow Inactive/Non-toxic: (Most common) e.g., Morphine to Morphine-3-glucuronide.

  • Active →\rightarrow Active: e.g., Morphine to Morphine-6-glucuronide (which is pharmacologically active).

  • Active →\rightarrow Toxic/Reactive: e.g., Paracetamol to NAPQI or Ethanol to Acetaldehyde.

  • Pro-drug →\rightarrow Active: e.g., Codeine to Morphine.

IV. Cytochrome P450 (CYP) Enzymes

  • Structure: Haem-containing proteins.

  • Classification: 57 genes, divided into 18 families and 43 subfamilies.

    • Naming: Superfamily (CYP) →\rightarrow Family (3) →\rightarrow Subfamily (A) →\rightarrow Gene (4).

    • Families CYP1, CYP2, and CYP3 are most important for drug metabolism.

  • Key Individual Enzymes:

    • CYP3A4: Responsible for a wide range of drugs due to broad substrate specificity.

    • CYP2D6: Involved in demethylation (e.g., codeine to morphine).

    • CYP2E1: Metabolises ethanol and converts paracetamol to NAPQI.

  • Research: Microsomes (fragments of the ER) are isolated from liver homogenates via ultra-high-speed centrifugation for in vitro studies.

V. Factors Modifying Metabolism and Interactions

  • Genetics: Individual variations in genes lead to different phenotypes:

    • Ultra-rapid metabolisers (UM): High activity; may lack therapeutic response as the drug is cleared too quickly.

    • Poor metabolisers (PM): Low/absent activity; risk of toxicity due to high plasma concentrations.

  • Drug Interactions (CC23): One substance alters the kinetics/action of another.

  • CYP Induction: A substance (e.g., Rifampicin, St. John’s Wort, chronic Ethanol) increases enzyme expression.

    • Outcome: Increased metabolism leads to reduced pharmacological effects.

  • CYP Inhibition: More common and clinically important. Drugs compete for an enzyme active site.

    • Competitive Inhibition: Reversible competition between drugs.

    • Mechanism-based Inhibition: Covalent bonding creates an irreversible complex (e.g., Ritonavir, Cobicistat).

    • Outcome: Reduced metabolism leads to increased plasma concentration and toxicity risk.

VI. Clinical Case Studies

  • Midazolam Interactions: Co-administration with Itraconazole (inhibitor) causes a massive rise in plasma levels, while Rifampicin (inducer) causes a significant drop.

  • Alcohol and Paracetamol:

    • Acute Alcohol: Competes for CYP2E1, actually reducing toxic NAPQI formation.

    • Chronic Heavy Drinking: Induces CYP2E1, increasing NAPQI formation and the risk of liver damage/death during a paracetamol overdose.

  • Pharmacokinetic Enhancers:

    • Ritonavir: Used at low doses in HIV treatment solely to inhibit CYP3A4 and "boost" the levels of other protease inhibitors like Saquinavir.

    • Cobicistat: Has no antiviral activity but is included in combination tablets (e.g., Stribild) to inhibit the metabolism of drugs like elvitegravir.