Drug Metabolism

• Drug metabolism


  The chemical transformation of a drug into one or more products within the body
• Drug metabolism


  • Does not occur for all drugs (like lithium)
  • Protects the body against xenobiotics (e.g., drugs, toxins)
  • Primarily occurs in the liver and other organs/tissues
  • First-pass (pre-systemic) metabolism (gut wall & liver) decreases bioavailability of orally administered drugs
• Drug metabolism


  • Mediated by enzymes
  • Involves oxidation, reduction, hydrolysis and/or conjugation
• Drug metabolising enzymes (DMEs)

  • Rich in liver
  • On membrane of ER of hepatocytes (liver cell like CYP450)
  • In cytosol (AD) or mitochondria (AldD) and other tissues/organs like the brain, lungs, plasma and intestines
• First pass


  The substance degradation of an orally administered drug caused by enzyme metabolism in the liver before the drug reaches the systemic circulation. It decreases the bioavailability of administered drugs
• Phase 1 Metabolism


  1. Oxidation, reduction, hydrolysis

  2. Parent drug (P1) metabolites (P2) conjugated metabolites
• Conjugated metabolites


  Virtually always inactive, very polar and/or ionized, and easily excreted. (Products of Phase II reactions)
• Phase 1 metabolism ethanol example

  1. Ethanol (CH3CH2OH)

  2. ADH (Alcohol Dehydrogenase) - removes H from parent drug

  3. Forms: Acetaldehyde (CH3CH2O)
• Phase 1 metabolism tenofovir disoproxil example hydrolysis

  1. Hydrolysis ester and (less readily) amide bonds

  2. Prodrug - a useful strategy to increase oral drug delivery

  3. Tenofovir Disoproxil

  4. esterase

  5. Tenofovir - not active and needs phosphorylation
• Phase 1 metabolism Codeine example Dealkylation

  1. Demethylation removing a methyl group

  2. Codeine

  3. CYP2D5

  4. Active Morphine
• Phase 2 metabolic reactions

  1. Glucuronidation (UGT)

  2. Sulfation (SULT)

  3. Glutathione conjugation (GST)
• Phase 2 metabolism


  • Conjugation reactions in which a polar molecule is linked to a suitable functional group on a drug or one of its Phase 1 metabolites
  • Attach a polar endogenous molecule to a functional group in a drug - increases hydrophilicity to facilitate excretion
• Glucuronidation


  UGT (UDP glucuronosyltransferase) transfers glucuronic acid from UDP-glucuronic acid to a drug or drug metabolite (UDP = uridine diphosphate)
• Sulfation


  SULT (Sulfotransferase) transfers sulfonate group from PAPS to a drug or drug metabolite (PAPS, 3'-phosphoadenosine–5'-phosphosulfate)
• Glutathione conjugation


  GST (glutathione-S-transferase) attach glutathione (Glu-Cys-Gly) to a drug or drug metabolite
• Morphine P2


  1. M -UGT2B7-> morphine-3-glucuronide (Major/pharm-inactive)

  2. M -UGT2B7-> morphine-6-glucuronide (Minor/Pharm-active)
• NAPQI (the toxic metabolite of paracetamol) - detoxification by glutathione conjugation
• Outcomes of drug metabolism

  • Increases molecular size and hydrophilicity
  • Decreases drug elimination half-life (t1/2)
  • Alters pharmacological activity or induces toxicity
• Increases molecular size and hydrophilicity

  • Reduces tendency to accumulate
  • Facilitates renal excretion
  • If drug is hydrophilic it doesn't undergo metabolism in liver and is removed by renal excretion
• Phase 1--> functional groups Lipophilic


  Goes through hepatic Metabolism to make hydrophilic metabolites that go through hepatobiliary excretion to either bile or renal excretion
• Decreases drug elimination half-life (t1/2) definition

  Drug elimination half-life (t1/2) is the time taken for the drug plasma concentration to decrease by 50% and is calculated during the elimination phase
• Plasma conc without drug metabolism

  Has a longer half life
• Plasma conc with drug metabolism

  Shorter half life
• Alters pharmacological activity or induces toxicity

  • Drug metabolism can terminate the action of a drug
  • Drug metabolism generates metabolites that have their own chemical properties and may be biologically active or inert
• Morphine


  • Morphine-3-glucuronide (inactive)
  • Morphine-6-glucuronide (active)
• Paracetamol


  • NAPQI (toxic)
• Codeine


  • Morphine (active)
• DMEs - cytochrome P450 (CYP)


  • Metabolism of drugs and xenobiotics - CYP1, CYP2 and CYP3
  • 57 CYP genes in human genome
  • Classified into 18 families and 43 subfamilies
• Key drug metabolising CYPs

  • CYP3A4
  • CYP2D6
• CYPs are ___-containing proteins

  Heme
• CYPs use _____ (cofactor) and __ to metabolise xenobiotics/drugs (SH)

  • NADPH
  • O2
  • 1 for oxidation
  • 1 added to H+ to make H2O
• CYP-POR (P450 oxidoreductase) complex- electron transfer

  1. NADPH

  2. FAD

  3. FMN

  4. P450
• CYP450 found on ____ ____ of hepatocytes

  • Endoplasmic reticulum (ER)
• Liver homogenates undergo sequential______ at ultra-high speed

  Centrifugation
• CYP450 concentrated in_____ (formed from ER fragments)

  Microsomes
• Microsomes


  Microsomes are small sealed vesicles that originate from fragmented cell membranes (often the endoplasmic reticulum [ER])
• Used in __ ____studies to investigate drug metabolism

  In vitro
• Drug interaction definition


  • Process by which a substance alters the action and/or kinetics of a drug
  • e.g., different CYPs have distinct but often overlapping substrate specificity
• Drug metabolism can be modified by endogenous and exogenous factors


  • Genetics, disease states and xenobiotics
• CYP-mediated drug-drug interactions


  • CYP induction
  • CYP inhibition