WEEK 2: DRUG ABSORPTION

• Drug absorption-> bioavailability determinant


  The transportation of the unmetabolized drug from the site of administration to the body circulation system
• Drug absorption curve - Phases


  1. Pre absorption phase-> time before drug enter systemic circulation

  2. Absorption phase

  3. Maximum concentration absorbed in plasma

  4. Biotransformation and pre-elimination phase

  5. Elimination Phase
• C max


  Maximum Plasma concentration - Drug absorption is good
• Minimum Plasma concentration


  Drug absorption is not good
• Absorption Principles


  • Diffusion, which depends on solubility (fat and/or water), molecular diameter, volatility, affinity
  • Absorption is influenced by amount of blood flow at the site of administration
• Absorption Barriers


  • Mucous layers
  • Membrane pores
  • Cell walls
  • First-pass metabolism
  • Placenta
  • Blood proteins
  • Fat isolation
  • Blood-brain barrier
• Exceptions to blood-brain barrier


  Area postrema, median eminence of hypothalamus
• Absorption Mechanics


  1. Water and fat solubility vary for each drug

  2. Relative solubilities (fat soluble % and water soluble %) depend on pH of the drug, pH of the solution, pKa of the drug

  3. Solubility percentages depend on ionization ratios
• Mechanisms of Drug Absorption


  • Passive diffusion
  • Pore transport
  • Facilitated diffusion
  • Active transport
  • Ion or electrochemical diffusion
  • Ionic-pair transport
  • Endocytosis
• Passive diffusion=> majority drug pathway


  1. Drugs must be first in aqueous solution to gain access to the lipid membrane

  2. Drugs pass along concentration gradient

  3. No energy or carrier is required

  4. It is not saturable

  5. It depends on

  • concentration gradient
  • lipid solubility=acidic drug in acidic envi. (stomach)/ basic drug in basic envi.(intestine)
  • degree of ionization
  • thickness of membrane
  • molecular size of the drug (up to 400 Daltons)
• Pore transport


  • Also called as convective transport, bulk flow or filtration
  • Responsible for the transportation of drug molecules via the protein channels into the cell
  • The hydrostatic pressure or the osmotic difference across the membrane constitutes the driving force the bulk flow of water through aqueous channels (aquaporins)
  • Less than 100 daltons
  • Depends on the number & size of the pores
• Facilitated diffusion


  1. Requires a carrier and it is saturable

  2. A carrier molecule is a transmembrane protein which binds one or more molecules or ions, changes conformation and releases them on the other side of the membrane

  3. Carrier molecules facilitate entry and exit of physiologically important molecules, such as sugars, amino acids, neurotransmitters and metal in the direction of their electrochemical gradient
• Active transport


  Drugs pass against concentration gradient, so it requires energy, carrier (thus it is saturable)
• Pinocytosis


  • Involves invagination of part of the cell membrane and the trapping of a small vesicle containing extracellular constituents within the cell
  • The vesicle contents can then be released within the cell, or extruded from its other side
• Pinocytosis


  • Pinocytosis of vitamin B12 (complexed with intrinsic factor)
  • Transport of some macromolecules (e.g. insulin, which crosses the blood–brain barrier by this process)
• Physico-chemical properties of drug


  • Molecular weight - Drugs with a small M.W. are absorbed well, Drugs which are large (often proteins) are absorbed poorly
  • Chemical and enzymatic stability - The drug should be stable in gastric acid and in gut enzymes
  • Aqueous and lipid solubility - For better absorption a drug must have optimum water and lipid solubility or a optimum partition coefficient

  = highly lipid soluble: drug not dissociate in circulation(ion trapping)

  = highly water soluble: drug not cross plasma membrane
• pH and lipid solubility


  Most drugs are either weak acids or weak bases and can exist in either the ionised (less lipid soluble) or unionized (more lipid soluble) form depending on the pH of the surrounding environment
• Ion Trapping


  Body fluids where a pH difference will favor trapping of highly lipophillic drugs: e.g. Breast milk, Aqueous humor (eye), Vaginal secretions, Prostatic secretions
• Ion Trapping


  • Aspirin is an acidic drug (pKa=5) and exist in the unionized form in stomach (pH 2.0)
  • In this form, it can enter the cells of the stomach lining (pH=7.4) where it is ionized and, in this form, it cannot leave the cell after becoming hydrophilic
  • The concentration of ionized aspirin inside the cell continues to rise until it saturates/ gives a good action and also precipitates as crystals, which lead to gastric bleeding
• Pharmaceutical factors affecting absorption


  • Disintegration time and dissolution time- compression variabilities
  • Manufacturing variables- compression variabilities
  • Pharmaceutical adjuvants – binding agents
  • Nature of dosage form- sustained release, enteric coated and pulsatile release
• Patient related factors affecting absorption


  • Age
  • Gastric emptying time
  • Gastric pH
  • Blood flow
  • Other enzymes
  • GIT diseases
• Conventional dose absorption


  Plasma drug concentration increases rapidly and then declines
• Sustained release/ enteric coated dose absorption


  Plasma drug concentration increases gradually and then declines slowly
• Pulsatile release dose absorption

  Plasma drug concentration shows multiple peaks
• Factors Influencing Absorption Rate

  • ROA
  • physicochemical properties of drug
  • dosage forms
  • circulation at the absorption site
  • drug concentration