Drug absorption – part II and first-pass metabolism Flashcards
Name the three times of route of admin:
- Paracellular
- Trans cellular
- Carrier mediated
Describe transcellular transport:
Through the cell.
Passive diffusion, active transport (e.g., PEPT1) or facilitated transport
- Follows concentration gradient
- Transport continues until equilibrium is reached
Transcellular transport dependent on:
- lipophilicity – more lipophilic more permeable
- molecular size –
- degree of ionisation
- molecular structure – H-donor/acceptor, functional groups
- surface area available – varies along the gut
- Slow movement
Describe paracellular transport:
Transport between epithelial cells
• Mainly via passive diffusion
• Important for polar hydrophilic drugs (and smaller)
Paracellular transport dependent on:
molecular size, size and density of the junctions, surface area
Effect of efflux transporters on bioavailability
Example Pgp (p glycoprotein)
- P-gp decreases concentration of drugs and metabolites in the enterocytes via active efflux into intestinal lumen
- Metabolite can also be effluxed by Pgp
P-glycoprotein-CYP3A4 (very widely expressed)interplay:
- recirculation of the drug
- increased exposure to CYP3A4
- generally leads to low F
- Inter-individual variability in drug absorption and F
Rate limiting steps in drug absorption?
Movement of drug across membrane may be rate limited by either:
1) Perfusion
or
2) Permeability
Perfusion rate limitation?
- Membrane offers no effective barrier to drug
- Molecule readily passes across membrane
- small lipophilic molecules (many drugs)
- very small hydrophilic molecules (water)
- Absorption rate varies with blood flow
Permeability limited absorption?
Molecule has difficulty passing across membrane - poor permeability
- Large polar hydrophilic molecules (most newly developed drugs)
- Absorption insensitive to changes in blood flow
- For acids and bases, ionization is an additional consideration
- unionized form of the drug assumed to be sufficiently lipophilic to cross the membrane
Drug release from formulation:
2 scenarios:
A. Permeability rate-limited absorption
B. Release/Dissolution rate-limited absorption (more common)
How to change/alter absorption and plasma concentration time profile of a drug?
- Modified/controlled release formulations – MR, CR
- Adjusted rate of release from the formulation
Does the permeability of intestinal wall membrane change along GIT?
- YES! Changes in permeability along GIT will affect rate limitation
- Important for sustained release formulations
- Poorly permeable drugs NOT good candidates for extended release formulations
- Expression of metabolic enzymes also varies
- Small intestine more permeable than large intestine
Structure of the gut?
Duodenum, jejunum , ileum and colon
Where is the gut has the highest CYP3A4 abundance?
Jejunum
What is Fg?
Fraction escaping intestinal metabolism
What is Fa?
Fraction absorbed
What is FH?
Fraction escaping hepatic metabolism
Implications of the intestinal first-pass?
- Can limit the value of the oral route - extensive metabolism in enterocytes (results in low FG )
- Significant contributor to low and variable F of a number of drugs (CYP3A- statins, HIV protease inhibitors; UGT- raloxifene)
- Transporter-metabolism interplay additional factor contributing to low F
- Inhibition of intestinal enzymes and transporters contributes to the extent of drug-drug interactions reported for many drugs
Cause of clinical drug-drug or drug-food interactions:
- Furanocoumarins present in grapefruit juice are irreversible inhibitors of intestinal CYP3A4
- Standard dose has no effect on hepatic CYP3A4
- Co-administration of grapefruit juice and CYP3A4 substrates (e.g., some statins) can:
- Prevent metabolism and elimination of the ‘victim’ drug
- Increase plasma concentrations of the ‘victim’ drug
- Recommended NOT to be taken with some statins!
Effect of grapefruit juice on simvastatin:
- Simvastatin – F<5%, extensive first-pass metabolism (intestine and liver)
- Grapefruit juice increases Cmax and AUC of simvastatin
- Leads to increased risk of adverse effects of simvastatin
Examples of drugs with low oral bioavailability due to extensive first-pass metabolism:
- Felodipine
- Simvastatin
- Atorvastatin
- Lovastatin
- Rifabutin
- Cyclosporine
- Tacrolimus
- Nisoldipine
- Sildenafil
- Verapamil
- Diltiazem
Factors affecting bioavailability – summary
- Incomplete absorption – decreases F
- -> Low intestinal permeability of large polar molecules (vancomycin)
- -> Poor dissolution (sparingly soluble drugs)
- Extensive first-pass metabolism in the intestine and liver - decreases F
- Inhibition of hepatic or intestinal first-pass - increases F
- Competing reaction – enzymatic (e.g., intestinal P450 and
efflux transporters) or non-enzymatic (complexation)* - Effect of surgery/disease status of the patient
- gastric bypass – decrease F or increase F
- coeliac disease, liver cirrhosis (mainly CYP3A substrates)
Intramuscular/Subcutaneous absorption principles:
- Same principles apply as for oral absorption
- Rate limited step will depend on the characteristics of the drug and the membrane
- Muscle capillary membrane
- -> Nature of barrier different to the gut wall - membrane is more porous, drugs more readily absorbed via paracellular route
- -> Generally perfusion rate limited
- Transdermal absorption (patches) – permeability rate limited absorption even for lipophilic compounds
Pulmonary absorption principles:
- Important for inhalers and treatment of respiratory diseases (asthma, chronic obstructive pulmonary disease)
- Rapid access to systemic circulation due to large surface area of lungs
- Avoids first-pass metabolism
- Disadvantage – commonly only 2-10 % aerosol dose deposited in lungs, 90% dose is swallowed!
- Deposition of inhaled particles depends on the particle characteristics, inhaling device and morphology of the respiratory tract
