ADME

• what is absorption?

  • how the drug gets into the systemic blood from it’s formulation at the administered site
  • movement into the body to the bloodstream
• what is distribution?

  • reversible transfer of drugs between the blood (systemic circulation) (or other side of measurement) and other issues within the body
  • movement around the body (through the circulatory system)
• what is metabolism?

  biotransformation of the drug into another chemical species - through enzyme mediated processes
• what is excretion?

  • irreversible loss of the drug from the systemic blood - through urine/sweat etc
  • movements out of body
• what is elimination?

  irreversible loss of a drug from site of measurement (e.g. plasma). Occurs by metabolism and/or excretion
• what is liberation?

  release of the drug from it’s dosage form - different to solubility and dissolution
• what does pharmacokinetics mean?

  what the body does to the drug
• name a few routes of drug administration...

  • enteral - oral, sublingual, rectal
  • parenteral - injections (intramuscular, subcutaneous, intravenous)
  • topical - epidermic, instillation, irrigation
  • inhalation - nebulisation, vaporisation
• why do have different routes of drug administration?

  • different routes can affect how quickly and effectively a substance reaches its target site
  • different routes can result in varying onset and duration of action
  • properties of the drug itself can influence the choice of route - some drugs are better absorbed through certain routes than others
  • avoidance of first-pass metabolism - so drug bioavailability less affected
• how does the drug get into the systemic blood from its formulation at the administered site: intravenous injection/infusion?

  direct to vein = direct to systemic circulation
• how does the drug get into the systemic blood from its formulation at the administered site: subcutaneous?

  • Low blood flow = slow absorption, either via diffusion/ permeation through the capillary wall, or via the lymphatic system
  • Used for large molecule/ biologic drugs, e.g., hormones [insulin], antibodies
• how does the drug get into the systemic blood from its formulation at the administered site: intramuscular?

  • High blood flow = fast absorption, via diffusion/permeation through the capillary wall
  • Used for large molecule/ biologic drugs (vaccines, antibodies) and antibiotics (streptomycin)
• how does the drug get into the systemic blood from its formulation at the administered site: oral (solution, capsule, tablet)?

  • Mouth → Oesophagus → Stomach → Small intestine → Large intestine → Faeces
  • Absorption to systemic circulation usually via the small intestine and hepatic portal vein
  • absorption has to happen faster than faeces production
  • common for small molecule drugs
• what drug and formulation properties of subcutaneous injections determine the place of absorption...

  • Molecular weight < 16 kDa: Diffusion/ permeation through the capillary wall is the dominant route of absorption (e.g. smaller proteins and peptides)
  • Molecular weight > 16 kDa: The lymphatic system is the dominant route of absorption
• what drug and formulation properties determine the absorption of oral solution/tablets/capsules?

  • Lipophilicity
  • Ionisation
  • Molecular weight
  • Solubility
  • Permeability
  • Formulation
• With the formulation of an oral drug, what parts of the formulation can influence the absorption?

  • Excipients
  • Enteric coating
  • Controlled release
  • Particle size
• absorption via transdermal patch...

  • Absorption requires permeation across/ into the outer epidermis (stratum corneum)
  • Patch can incorporate chemical and physical methods to enhance drug penetration/permeation
  • Hydration of stratum corneum
• what does distribution determine?

  • Determines drug concentration in the blood plasma and different tissues
  • unbound drug concentration drives effect! (these can only reach the cells and go in and reach receptors)
  • unbound drug usually one to be metabolised and excreted
• tissue perfusion: highly perfused...

  • equilibrium - fast (when looking at drug concentration)
  • these organs have a high rate of blood flow and receive a large amount of oxygen and nutrients
  • blood flow is very high relative to the size of the organ
• what organs are highly perfused?

  lungs, kidneys, liver, brain
• examples of poorly perfused...

  muscle, skin, adipose (connective tissue)
• poorly perfused...

  equilibrium is slow
• Plasma protein binding can allow for what?

  allows measurement of drug binding using dialysis -

  • semi-permeable membrane allows drug that unbound to diffuse through the membrane
  • proteins and proteins with drug bound don’t diffuse through and so the concentration of unbound proteins can be measured
• name an example of a key drug-binding plasma protein...

  albumin - synthesised in the liver
• what does drug metabolism involve?

  • involves enzyme-mediated chemical reactions
• what are the general trends relating to drug metabolism?

  • metabolites are usually more polar and less lipophilic than the parent drug
  • so less lipophilic = decreased permeability and increased aqueous solubility
  • less lipophilic metabolite more likely to be excreted
  • opposite may apply to prodrugs
• which organs are the key sites for first-pass drug metabolism?

  liver and intestine (for oral administration)
• where does oral administration have to go through first before it gets into systemic circulation?

  GI tract - through enterocytes

  and so gets metabolised first in the liver before hit enters the systemic circulation
• what is a prodrug?

  Inactive form of a drug that is converted into an active form in the body - it gets metabolised to become active
• what are some factors that affect drug metabolising enzymes?

  • age
  • gender
  • drug-drug interaction
  • polymorphism
  • diabetes miletus
  • kidney diseases
  • liver diseases
  • organ transplant
  • inflammatory mediators