Drug absorption – part II and first-pass metabolism

Question 1

Name the three times of route of admin:

Answer 1

• Paracellular
• Trans cellular
• Carrier mediated

Question 2

Describe transcellular transport:

Answer 2

Through the cell.

Passive diffusion, active transport (e.g., PEPT1) or facilitated transport

• Follows concentration gradient
• Transport continues until equilibrium is reached

Question 3

Transcellular transport dependent on:

Answer 3

• 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

Question 4

Describe paracellular transport:

Answer 4

Transport between epithelial cells
• Mainly via passive diffusion
• Important for polar hydrophilic drugs (and smaller)

Question 5

Paracellular transport dependent on:

Answer 5

molecular size, size and density of the junctions, surface area

Question 6

Effect of efflux transporters on bioavailability

Answer 6

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

Question 7

P-glycoprotein-CYP3A4 (very widely expressed)interplay:

Answer 7

• recirculation of the drug
• increased exposure to CYP3A4
• generally leads to low F
• Inter-individual variability in drug absorption and F

Question 8

Rate limiting steps in drug absorption?

Answer 8

Movement of drug across membrane may be rate limited by either:
1) Perfusion
or
2) Permeability

Question 9

Perfusion rate limitation?

Answer 9

• 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

Question 10

Permeability limited absorption?

Answer 10

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

Question 11

Drug release from formulation:

2 scenarios:

Answer 11

A. Permeability rate-limited absorption

B. Release/Dissolution rate-limited absorption (more common)

Question 12

How to change/alter absorption and plasma concentration time profile of a drug?

Answer 12

• Modified/controlled release formulations – MR, CR

- Adjusted rate of release from the formulation

Question 13

Does the permeability of intestinal wall membrane change along GIT?

Answer 13

• 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

Question 14

Structure of the gut?

Answer 14

Duodenum, jejunum , ileum and colon

Question 15

Where is the gut has the highest CYP3A4 abundance?

Answer 15

Jejunum

Question 16

What is Fg?

Answer 16

Fraction escaping intestinal metabolism

Question 17

What is Fa?

Answer 17

Fraction absorbed

Question 18

What is FH?

Answer 18

Fraction escaping hepatic metabolism

Question 19

Implications of the intestinal first-pass?

Answer 19

• 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

Question 20

Cause of clinical drug-drug or drug-food interactions:

Answer 20

• 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!

Question 21

Effect of grapefruit juice on simvastatin:

Answer 21

• 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

Question 22

Examples of drugs with low oral bioavailability due to extensive first-pass metabolism:

Answer 22

• Felodipine
• Simvastatin
• Atorvastatin
• Lovastatin
• Rifabutin
• Cyclosporine
• Tacrolimus
• Nisoldipine
• Sildenafil
• Verapamil
• Diltiazem

Question 23

Factors affecting bioavailability – summary

Answer 23

• 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)

Question 24

Intramuscular/Subcutaneous absorption principles:

Answer 24

• 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

Question 25

Pulmonary absorption principles:

Answer 25

• 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