Drug absorption and first pass metabolism Flashcards
What are the rate limiting steps for oral absorption?
Movement through membranes
a) perfusion OR
b) permeability limitations
What is the transcellular route ?
Through the cell via passive diffusion, active transport (e.g. PEPT1) or facillitated transport
- follows concentration gradient
- transport continues until equilibrium is reached
What does transcellular transport depend on?
- lipophilicity – more lipophilic more permeable
- molecular size –
- degree of ionisation (slow movement for large, polar and charged molecules)
- molecular structure – H-donor/acceptor, functional groups
- surface area available – varies along the gut
What is the paracellular route?
Transport between epithelial cells:
- mainly via passive diffusion
- important for polar hyrdophilic drugs
What is the paracellular route dependent on?
- molecular size
- size and density of junctions
- surface area
What is P-gp and where is it found?
Efflux transporter located on the apical membrane of enterocytes, biliary canalicular membrane of hepatocytes and other tissues
What effect does P-gp have on bioavailability?
P-gp decreases concentration of drugs and metabolites in the enterocytes via active efflux into intestinal lumen
What is the P-glycoprotein-CYP3A4 interplay?
Drugs are metabolised by CYP3A4 enzymes and the metabolite is effluxed by P-gp
What does the P-glycoprotein-CYP3A4 interplay lead to?
- Recirculation of the drug
- Increased exposure to CYP3A4
- Generally leads to low F (e.g. saquinavir, atorvastatin)
- Inter-individual variability in drug absorption and F
What can movement of drug across the membrane be rate limited by?
Either perfusion or permeability
Slowest process = rate limiting
What is perfusion?
- Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue.
- Membrane offers no effective barrier to drug
What sort of molecules have good perfusion?
Small lipophilic molecules (many drugs) and very small hydrophilic molecules readily passes across membrane
What varies absorption of drug via perfusion?
Blood flow (rate limitation)
What is permeability limited absorption?
When a molecule has difficulty passing across membrane - poor permeability
What types of molecules have poor permeability?
Large polar hydrophilic molecules (most newly developed drugs)
