Drug absorption Flashcards
What sequence does a drug follow after oral administration?
dissolves in GI lumen, absorption across gut wall, liver, systemic circulation
Definition of absolute bioavailability?
usually assessed with reference to an intravenous dose
Definition of relative bioavailability?
Comparison of the bioavailability between formulations of a drug given either by the same or different routes of administration
Definition of bioequivalence?
Formulations containing the same dose of same chemical entity, generally in the same dosage form, intended to be interchangeable
Which parameters define bioequivalence?
Cmax - highest concentration reached in plasma
AUC - area under the plasma concentration time curve
If plasma concentration-time profiles are similar - less likely to cause clinically relevant differences in therapeutic and adverse effects
Possible rate limiting steps for oral drug absorption?
- disintetgration/dissolution time
- gastric emptying and intestinal transit
- movement through membranes (perfusion or permeability)
- first pass metabolism in gut/liver
Role of gastric emptying in drug absorption?
controls the rate of delivery of drug to the small intestine, and affects rate of absorption
Factors affecting gastric emptying?
- co-administration of other drugs
- food
- age
Effect of metoclopramide on gastric emptying?
faster emptying, so faster absorption of drugs co-administered with metoclopramide. higher Cmax, lower Tmax
Effect of anticholinergic on gastric emptying?
slower gastric emptying - lower Cmax and longer Tmax
Effect of gastric emptying on AUC?
None, same amount of drug absorbed just at a different rate
Effect of food on gastric emptying?
transit time increases with size of meal vs fasted or light meal - no significant effect on transit time of small intestine
more variability for large particles than small
Purpose of enteric coating?
to be given on a fasted stomach - drug sensitive to stomach pH. coating won’t last the full delayed transit time if not given fasted
Purpose of drugs given with food?
For poorly soluble drugs, delayed time increases exposure so more can dissolve before entering small intestine
Effects of gastric bypass on drug absorption and bioavailability?
pH changes and reduced surface area of stomach. bypasses main areas of absorption (duodenum and jejunum, approx 75cm)
still limited data on drug absorption - contradictive results.
Effects of coeliac disease on drug absorption and first pass metabolism?
- severely reduced CYP3A in intestine
- limited data on the effect of the disease on other metabolic enzymes
Effects of liver disease on drug absorption and first pass metabolism?
Reduced activity of metabolic enzymes, extent depends on the severity
Effects of chronic kidney disease on drug absorption and first pass metabolism?
evidence suggests increase pH and gastric emptying time, changes in expression of some CYP450 enzymes
Movement of solubilised drugs in intestine?
- diffusion between cells (paracellular)
- diffusion through cells (transcellular)
- transporters (uptake and efflux)
How does transcellular transport of drugs occur?
passive diffusion follwing concentration gradient, until equilibrium is reached
more lipophilic compounds more permeable, smaller size more preferable, degree of ionisation (unionised more lipophilic)
How does paracellular transport of drugs occur?
mainly via passive diffusion, important for polar/hydrophilic drugs. dependent on molecule size and size of juncitons, quite tight in intestine so less common
Effect of efflux transporters on bioavailability?
Pump out drugs from cells back into lumen of intestine, so cannot be absorbed into the blood. New drugs must be screened for listed clinically relevant transporters, as this must be accounted for in formulation and dosing
Effect of P-gp on bioavailability?
P-gp is located on the apical (lumen) membrane of intestine, biliary membrane and some other tissues.
Active efflux back into lumen of intestine
P-gp and CYP3A4 interplay?
Recirculation (uptake and efflux) of drug leads to increased exposure to CYP3A4 so more metabolism before systemic circulation - lower F.
Large interpatient variability in drug absorption
What can limit the movement of the drug across a membrane?
Perfusion or permeability
How can perfusion limit movement of a drug?
If the membrane offers no effective barrier to the drug, it passes readily across (e.g. small lipophilic, v small hydrophilic). absorption rate varies with blood flow
What kinds of drugs readily cross membranes?
Small lipophilic, very small hydrophilic
How can permeability limit movement of a drug?
Molecule has difficulty passing across the membrane.
- absorption insensitive to changes in blood flow
- ionisation is an additional consideration for acids and bases
- unionised form of a drug is usually considered lipophilic enough to cross membranes
What kinds of drugs have permeability difficulties?
Large polar hydrophilic molecules
Difference between permeability rate limited absorption and release/dissolution rate limited absorption?
Permeabilty - driven by physchem properties of the drug. Release/dissolution driven by formulation
What are some benefits of release/dissolution rate limited absorption?
Utilised in modified release formulations, can adjust the rate of release. Affects the absorption and plama/time curve - with less fluctuation between cmax and cmin
- different dosing interval
How does permeability change along the GIT?
highest permeability is in the upper region of the small intestine, then decreases as you go down. distal regions of large intestine are not very permeable
Why are poorly permeable drugs not good candidates for extended release formulations?
Drug continues to be released in the less permeable regions of the intestine, so won’t be absorbed well
expression of metabolic enzymes also changes along the GIT
Typical characteristics of poorly permeable drugs?
large, bulky, ionised hydrophilic molecules e.g. vancomycin
