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)
Does blood flow affect permeation absorption?
NO - Absorption insensitive to changes in blood flow
Does the permeability of intestinal wall membrane change along the GIT?
YES - changes in permeability along GIT will affect rate limitation.
Expression of metabolic enzymes also varies
Are poorly permeable drugs good candidates for extended release formulations?
NO
What drugs show low oral bioavailability (examples)?
- Amikacin
- Gentamicin
- Vancomycin
- Neomycin
- Streptomycin
etc
Bioavailability equation for first pass metabolism?
F = Fa.Fg.Fh
Fa - fraction absorbed through the membrane into the enterocyte)
Fg - Fraction escaping intestinal metabolism
Fh - Fraction escaping hepatic metabolism
A drug has an Fg value of 0.15. What can be deduced about its 1st pass from this information?
pronounced intestinal first pass (lower the value the lower the amount that is escaping first pass) only 15% is escaping intestinal metabolism
–> Therefore the drug would have low bioavailability
What does extensive metabolism in enterocytes result in ?
Low Fg (intestinal metabolism) - and therefore contributing to low F
What does the inhibition of intestinal enzymes and transporters contribute to?
DDIs reported for many drugs
What food/drink selectively inhibits intestinal CYP3A4?
Grapefruit juice (irreversible inhibitors), with no effect on hepatic CYP3A4
What can co-administration of grapefruit juice and CYP3A4 substrates (e.g. statins) do?
- prevent metabolism and elimination of the ‘victim’ drug
- Increase plasma concentrations (Cmax) of the ‘victim drug’
- hence why it’s recommended to NOT take with some statins
What are some examples of drugs with low oral bioavailability due to extensive first pass metabolism?
- saquinavir
- felodipine
- simvastatin
- atorvastatin
- lovastatin
- rifabutin
- cyclosporine
- tacrolimus
- sildenafil
- verapamil
- diltiazem
What formulation gives higher F of drugs with extensive intestinal 1st pass?
MR e.g. oxybutynin
What is the nature of the muscle capillary membrane in IM/Sc absorption?
- Nature of barrier different to the gut wall - membrane is more porous, drugs more readily absorbed via paracellular route
- generally perfusion rate limited
What is pulmonary absorption
- important for inhalers and treatment of respiratory diseases (asthma, COPD)
- rapid access to systemic circulation due to large SA of lungs
What is an advantage of pulmonary absorption?
Avoids first pass metabolism
What is a disadvantage of pulmonary absorption?
commonly only 2-10 % aerosol dose deposited in lungs, 90% dose is swallowed!
