Lecture 3

• Metabolism

  Irreversible biochemical transformation of drug into metabolites to increase excretion from the body [mostly via the kidney]
• Metabolism/biotransformation/chemical-alteration


  • Occurs mainly in the liver
• Drug


  Usually converted to a more water-soluble compound
• Metabolite

  • Activity may be different from parent compound
  • Usually more polar (ionised)
  • Usually less lipid soluble
  • Renal tubular absorption decreases
  • Less likely to bind to plasma proteins
  • Less likely to be stored in fat
• Liver


  • The dominant organ in drug metabolism, but not the only organ
• Importance of drug metabolism

  • Understanding the pharmacological and toxicological activity of drugs
  • Shortening the toxin/drug's duration of action
  • Complications of drug-drug interactions mainly depends on the induction in inhibition of metabolic enzymes
• Metabolism may result in

  • Active drug → inactive metabolite (most common)
  • Inactive drug → active drug (prodrug converted to active drug)
  • Active drug → active metabolite (adds another step before excretion and prolongs drugs' actions)
• Prodrug


  Drugs which don't have any activity in vitro, may gain activity after their biotransformation in the body
• Drug examples

  • Drugs that gain activity after biotransformation (pro-drugs)
  • Drugs that are transformed to more active compounds after biotransformation
  • Drugs that are transformed to less active compounds after biotransformation
  • Drugs that are transformed to inactive metabolites after biotransformation (detoxification)
• First-pass effect

  • Drugs taken orally pass through the liver before they get to the systemic circulation
  • During first pass through the liver, drug is removed by metabolism or hepatobiliary secretion
• Phases of metabolism

  • Phase I, oxidation, hydrolysis and reduction (non-synthetic reactions)
  • Phase II, conjugation (synthetic reactions)
• Phase I metabolism

  Metabolises drugs to create sites for phase II metabolism
• Phase I oxidation

  • Mediated predominantly via microsomal endoplasmic reticulum cytochrome P450 liver enzymes
  • Kidney and nervous tissue enzymes can also oxidise compounds
  • Includes oxidative dealkylation, oxidative deamination, N and S oxidation, alcohol/aldehyde dehydrogenase
• Phase I reduction


  • Mediated by P450 enzymes
• Phase I hydrolysis

  • Performed by hydrolytic enzymes called plasma esterases e.g. plasma cholinesterase
• Cytochrome P450 enzymes

  • Located in hepatic microsomes
  • Have low substrate specificity
  • Show high affinity to high lipophilic molecules
  • Require NADPH and molecular oxygen (O2) for activity
  • Cytochrome P450 is a 'haem' containing protein
  • The active site is the Fe ion in the Fe3+ form
• Cytochrome P450 catalytic cycle

  1. Enzyme-drug complex formation

  2. Electron transfer from NADPH

  3. Enzyme-drug-O2 complex formation

  4. Complex breakdown into oxidised enzyme, water and oxidised drug
• Important cytochrome P450 enzymes

  • CYP1A2
  • CYP2C9
  • CYP2C19
  • CYP2D6
  • CYP3A4
• Phase II metabolism


  • Conjugation reactions
  • Couples agent to existing (or phase I formed) conjugation site on drug/metabolite
  • Involves addition to functional groups including ethers, alcohols, aromatic amines
• Phase II conjugation reactions

  • Glucuronidation
  • Sulphate conjugation
  • Acetylation
  • Methylation
  • Glutathione conjugation
  • Amino acid conjugation
• Glucuronidation


  • Catalysed by UDP-glucuronosyltransferases (UGTs) in the ER of liver cell
  • Decreases the lipid solubility of the drug, making excretion easier
• UGT enzymes


  • Make phase II conjugation possible by providing functional groups from phase I
  • Involved in bilirubin elimination and neurotoxicity in context of UGT1A1 defect
• Sulfotransferase enzymes


  • Catalyse the second important conjugation reaction after glucuronidation
• Factors causing variable metabolism


  • Age
  • Gender
  • Disease states (liver disease, etc)
  • Drug tolerance
  • Genetic differences (expression/efficiency)
  • Species (human/animals/etc)
  • Inducers/inhibitors
  • Diet
  • Drug-drug interactions
• Polymorphism


  DNA sequence variation that is common in the population, leading to different enzyme activity
• Examples of polymorphism effects


  • Hydrolysis of succinylcholine (atypical cholinesterase)
  • Acetylation of isoniazid (slow vs rapid acetylators)
  • CYP2D6 polymorphism (affecting metabolism of many drugs)
• CYP2D6 phenotypes


  • Poor metabolizers
  • Intermediate metabolizers
  • Extensive metabolizers
  • Ultrarapid metabolizers
• Enzyme induction


  Increases in the activity of enzymes due to increased synthesis, leading to increased metabolism and reduced drug effects
• Enzyme inhibition


  Decreases in the activity of enzymes, leading to decreased metabolism and increased drug effects
• Liver disease


  • Decreases metabolism of drugs with high hepatic clearance, leading to accumulation and increased effects/adverse effects
  • Decreases transformation of prodrugs into active forms
• Age and gender


  • Foetus has only CYP3A, low phase II enzymes - high risk of toxicity
  • Newborns have immature enzymes - slow biotransformation
  • Elderly have reduced enzyme activity, especially in males - reduced first pass metabolism
• Nervous System


  Consists of all the nerve cells. It is the body's speedy, electrochemical communication system
• Central Nervous System (CNS)

  The brain and spinal cord
• Peripheral Nervous System (PNS)

  The sensory and motor neurons that connect the central nervous system (CNS) to the rest of the body
• Brain

  • Controls both voluntary actions, like talking and running, and involuntary actions like breathing and reflexes
  • Our emotions, memory and personality as well as our senses —sight, touch, hearing, taste, smell— originate in our brain
  • The brain works as a single organ but is divided into areas of special expertise and function
• Three major parts of the brain

  • Forebrain
  • Midbrain
  • Hindbrain
• Forebrain


  • Thought and planning, Memory formation and retrieval, Sensory processing, Language processing, Emotion regulation
• Midbrain


  • Relaying sensory information, Coordinating movement, Maintaining alertness
• Hindbrain

  • Regulating vital functions, Balance and coordination, Reflex
• Grey matter

  The tissue called "gray matter" in the brain and spinal cord is also known as substantia grisea, and is made up of cell bodies