lesson 4

• Distribution

  1. Drug reaches the target site

  2. Process by which a drug reversibly leaves the bloodstream and enters interstitium and cells of tissues
• Liberation

  1. Release of drug from its dosage form for it to be absorbed by the body

  2. 2 prerequisites for absorption: Must be in unionized form, Must be in aqueous form, Dissolution – rate-limiting step in absorption, Exception: true solutions
• Factors affecting Absorption

  • Chemical structure
  • Variation in particle size and surface area
  • Nature of crystalline form
  • Type of tablet coating
  • Type of tablet matrix
• Factors affecting Liberation

  • Formulation of salts for easy absorption
  • Formulation of a prodrug
  • To enhance absorption
  • To facilitate drug reaching the target site
  • To alter solubility
  • To facilitate formulation into a dosage form
  • To alter distribution and t1/2
• Factors affecting Distribution

  • Blood flow
  • Capillary permeability
  • Protein binding
  • Affinity of drug to fat deposits
  • Drug receptor interactions
• Pharmacodynamics


  • What the drug does to the body
  • Deals with the interaction of drugs with receptors, the molecular consequences of these interactions and their effects on the patient
  • By binding to enzymes
  • By binding to nucleic acids
  • By binding to membrane receptors
• Pharmacokinetics


  • What the body does to the drug
  • Physicochemical properties of the drug affecting biological action
  • LADME (Liberation, Absorption, Distribution, Metabolism, Excretion)
• Organic Medicinal Chemistry


  • Deals with the physicochemical properties of drugs that affect its biological action
• Metabolism

  1. First-pass effect, A phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation, PO, PR

  2. Enterohepatic circulation (biliary recycling), Phenomenon in which drugs emptied via bile into the small intestine can be reabsorbed back into the circulation, Extended duration of action and t1/2
• Phase I


  Aka: Functionalization phase, Introduce a polar functional group into a xenobiotic molecule, Enzymes: microsomal mixed function oxidases or monooxygenases
• Absorption

  1. Drug enters the systemic circulation

  2. Exemption: IV drugs, IV > solution > suspension > capsule > tablet
• Phases of Metabolism

  • PHASE I
  • PHASE II
• Phase I Reactions

  Oxidation - most common
• CYP Family of Isoenzymes

  • CYP450 – most important & most abundant
  • CYP1A2 – Acetaminophen, Theophylline
  • CYP2C9 – Warfarin, Phenytoin
  • CYP2C19 – Omeprazole, Propranolol
  • CYP2D6- Tamoxifen, Codeine, Metoprolol, Anti-arrhythmics, Antipsychotics, Antidepressants
  • CYP3A4- Macrolides, Amiodarone, Azoles, Grapefruit juice
• Areas of Discipline in Drug Metabolism

  • Pharmacokinetics
  • Pharmacodynamics
• Oxidation


  • Alcohols → Acids
  • Olefins → Epoxides
  • Oxidative N, O, S dealkylation to give NH2, OH, SH
  • Oxidation of aromatic compounds
  • Aliphatic hydroxylation, deamination, desulfuration, dechlorination
• Phase I Reactions

  1. Oxidation - most common

  2. Reduction

  3. Hydrolysis
• Oxidation of Aromatic Moieties

  • Aromatic Hydroxylation - Major route of metabolism, mostly occurs at PARA position, occurs readily at activated/electron-rich rings
• Cytochrome P450 enzymes and their substrates

  • CYP1A2 - Acetaminophen, Theophylline
  • CYP2C9 - Warfarin, Phenytoin
  • CYP2C19 - Omeprazole, Propranolol
  • CYP2D6 - Tamoxifen, Codeine, Metoprolol, Anti-arrhythmics, Antipsychotics, Antidepressants
  • CYP3A4 - Macrolides, Amiodarone, Azoles, Grapefruit juice
• Hydrolytic Reactions


  • For esters and amides, important for prodrugs
• Phase II Reactions

  Attach a small, polar, ionizable endogenous compound to the functional handles of Phase I to make it water-soluble conjugated product, usually but not always result in inactive products
• Phase II Reactions

  • Glucuronidation, Sulfate Conjugation, Glutathione conjugation, Glycine & Glutamine conjugation, Methylation, Acetylation
• Oxidation Involving C-Heteroatom Systems

  • Carbon-Nitrogen, Carbon-Oxygen, Carbon-Sulfur
• Glucuronidation


  • Most common conjugative pathway, generally increases water solubility of xenobiotics and endogenous compounds, not developed in neonates, should be initially activated prior to transfer, Coenzyme: UDPGA (uridine-5’-diphospho-α-D-glucuronic acid), Catalyzed by the enzyme UDP-glucuronyltransferase
• Sulfate Conjugation

  • Only pathway well-developed in neonates, occurs primarily with phenols
• In fetal & newborn animals, underdeveloped/deficient oxidative and conjugative enzymes
• Coenzyme

  UDPGA (uridine-5’-diphospho-α-D-glucuronic acid)
• Acetylation


  1. Minor metabolic pathway

  2. Important route for drugs containing 1o amino groups of aromatic amines

  3. Function: termination of pharmacologic action or detoxification

  4. Source: Acetyl-CoA

  5. Subject to genetic polymorphism (fast/rapid and slow acetylators)
• In humans, for oxidative metabolism: Tolbutamide (for diabetes) – in infants (within 40 hours); in adults (within 8 hours)
• Conjugation with sulfate

  1. Only pathway well-developed in neonates

  2. Occurs primarily with phenols, occasionally with alcohols, aromatic amines and N-hydroxy compounds
• Conjugation with glycine, glutamine and other amino acids

  1. Glycine: for acids (aromatic & aryl alkyl acids)

  2. Glutamine: for aryl acetic acids
• Glutathione conjugation or mercapturic acid conjugates


  1. Important for detoxifying chemically reactive electrophilic compounds & metabolites

  2. Conjugated with GSH usually are not excreted as such, but undergo biotransformation to products called mercapturic acids

  3. GSH (a tripeptide) protects vital cellular constituents by virtue of its nucleophilic SH group

  4. Don’t require initial activation of coenzymes (only by GSH S-transferases)
• Examples: Hexobarbital, Tolbutamide, Chloramphenicol and Bilirubin
• Hexobarbital (a sedative): In newborn mice, drug is metabolized slowly within 6 hours; In adult mice, drug is metabolized faster (<5 minutes)
• Methylation


  1. Important in the biosynthesis of many endogenous compounds, inactivation of physiologically active biogenic amines (e.g. NE, dopamine, 5-HT)

  2. Coenzyme: SAM (S-adenosylmethionine)

  3. Transfer is catalyzed by methyltransferases (e.g. COMT, POMT, non-specific N-methyltransferase and S-methyltransferases)
• Factors affecting metabolism

  • Age
  • Species & strain differences
  • Hereditary or Genetic factors
  • Sex differences
  • Enzyme induction and enzyme inhibition
• Conjugation with sulfate

  1. Transfer of sulfate to the substrate is catalyzed by sulfotransferases

  2. Limited availability
• Bilirubin (an endogenous compound; a normal by-product of hemoglobin breakdown) – a nonpolar compound, can cross the blood brain barrier
• In infants, no glucuronidation, bilirubin cannot be metabolized → toxic effects and levels of drugs → can cross the blood brain barrier (BBB) and accumulates in the brain causing kernicterus/neonatal hyperbilirubinemia
• In humans, for glucuronidation: Chloramphenicol – in infants, no glucuronidation (low levels of enzymes) – toxic levels of drugs (Gray Baby Syndrome)