basics - drug absorption/bioavailability

• define 'absorption of drug'

  movement of the drug from the site of administration into the blood (or lymph), usually across a membrane (not really applicable for intravenous)
• important drug-specific properties for determining routes of administration:

  • Lipophilicity
  • Ionisation at relevant pH
  • Solubility
  • Permeability
  • Route of elimination
  • Active transport
• important formation-specific properties to enable the selected route of administration:

  • release from formulation
  • solubilising components
• define bioavailability

  the extent of absorption of the intact drug. Fraction of an extravascularly administered dose reaching the systemic circulation intact.
• what can bioavailability be represented as?

  • can be represented as a number/fraction
  • F - has a value between 0 and 1, or is expressed in % - 0.5 = 50% bioavailability of the drug
• define absolute bioavailability

  usually assessed with reference to an intravenous dose (100% of the dose goes into the blood). Measure other administration bioavailability compared to intravenous.
• define relative bioavailability

  Comparison of the bioavailability between formulations of a drug given either by the same or different routes of administration
• define absorption

  how the drug gets into the systemic blood from it’s formulation at the administered site
• why is bioavailability important?

  Drug concentration in blood plasma and site of action needs to be high enough to have pharmacological response.
• advantage of intravenous administration:

  • Gold standard for comparing other routes
  • Absorption of the drug is complete
• limitation of intravenous administration:

  Can be invasive for the patient
• advantages and limitations of oral administration:

  • Convenient, most frequent, generally safe
  • Extent of the drug reaching systemic circulation can be reduced due to the first-pass effect (metabolism of the drug) or inappropriate drug formulation
  • The onset of effect can be slow (may be desirable)
• Why are biologics drugs such as monoclonal antibodies and hormones not usually administered orally?

  • all proteins
  • in acidic environments, they get denatured reducing bioavailability
  • enzymes digest proteins → peptidases/proteases (pepsin) break them down into peptides then amino acids and so antibody unable to be taken into the enterocytes and reach the systemic circulation
  • also, they’re large so not permeable - never fast enough to get absorbed through the membrane
• what are the potential barriers to oral bioavailability?

  1. Disintegration (release of the drug from solid-state) time and dissolution rate [liberation]

  • Solubility and precipitation

  1. Gastric emptying and intestinal transit
  2. Passive and active movement of drug across the membrane of the intestinal wall
  3. First-pass metabolism in the intestine and liver
• drugs -> gut wall -> portal vein -> liver -> systemic circulation
• the process...

  A) disintegration

  B) deaggregation

  C) dissolution

  D) portal

  
• 1. Disintegration and dissolution (properties and physiology that impact this)

  drug properties:

  • pKa
  • lipophilicity
  • solubility

  formulation properties:

  • excipients
  • enteric coating

  physiology:

  • stomach vs intestine
  • pH
  • bile
  • fasted vs fed
  • gastric emptying
  • GI motility
• how does bile enhance drug solubility?

  1. Bile acids form micelles

  • has hydrophobic and hydrophilic regions

  1. Lipophilic drug preferentially distributes into the lipid core of the micelle

  • micelle can naturally form if there are many bile acids
  • used to improve the solubility of the lipophilic drug

  1. Bile acts as a natural surfactant
• no bile = reduced bioavailability
• what features help increase the permeability across the intestinal wall?

  Intestine anatomy yields large surface area - microvilli and vili
• transcellular transport depends on:

  • lipophilicity of the drug
  • molecular size - increased size = decreased permeability
  • degree of ionisation
  • surface area available– varies along the gut

  Slow movement for large, polar and more charged molecules
• intestine has good blood flow - leaves the gut very quick and so maintains the concentration gradient 
• importance of drug properties: Lipinski's rule of five-

  An orally administered drug should not violate more than one of the four following criteria:

  • No more than 5 hydrogen bond donors
  • No more than 10 hydrogen bond acceptors
  • Molecular weight less than 500 g/mol
  • LogP not greater than 5
• what is the first-pass metabolism?

  loss of a drug as it passes through intestine and liver during absorption (pre-systemic metabolism)
• for first-pass metabolism - it's predominately occurring via what enzyme?

  via CYP3A4 (Cytochrome P450 3A4 - metabolic enzyme)
• Extensive first pass metabolism will reduce the bioavailability of a drug
• Examples of drugs with low bioavailability due to high first-pass metabolism:


  • atorvastatin
  • lovastatin
  • saquinavir
  • felodipine
  • rifabutin
  • cyclosporine
  • tacrolimus
  • sildenafil
  • nisoldipine
  • verapamil
  • diltiazem
• factors affecting drug dissolution in GI tract:

  • pH
  • fluid volume/contents
  • transit time
  • bile
• factors affecting permeation:

  • pH
  • surface area of the intestine
  • transit time
• Effects of gastric bypass surgery on drug absorption-

  • Large physiological changes - reduction in surface area of the stomach, pH changes
  • Bypass of main areas of drug absorption
  • – e.g., duodenum and the jejunum (~75cm bypassed)