Drug Absorption

Question 1

what is the rate limiting steps for oral absorption?

Answer 1

A. Disintegration time and 
    dissolution rate*
B. Gastric emptying and intestinal 
    transit
C. Movement through membranes 
    a) perfusion  or   
    b) permeability limitations
D. First-pass metabolism in the 
    gut/liver

Question 2

what are the characteristics of the intestinal lumen?

Answer 2

very thin layer - multiple ways the drug move through reach systemic circulation,.

• transcellular
• paracellular
• transporters

Question 3

what is transcellular transport/

Answer 3

through the cell

passive diffusion, active transport or facilitated transport.

Question 4

what is transcellular transport dependent on?

Answer 4

 lipophilicity – more lipophilic more permeable
 molecular size –
 degree of ionisation
 molecular structure – H-donor/acceptor, functional groups
 surface area available – varies along the gut

Question 5

what is paracellular?

Answer 5

transport between epithetlial cells
	Mainly via passive diffusion
	Not a dominant process
	Important for polar hydrophilic drugs
	Dependent on: molecular size, size and density of the junctions, surface area

Question 6

what are effect of efflux transporters on bioavailbility?

Answer 6

P-glycoprotein (P-gp) - located on the apical membrane of enterocytes, biliary canalicular membrane of hepatocytes + other tissues!

Question 7

what is the effect of P-gp on bioavailabilty?

Answer 7

P-gp decreases concentration of drugs and metabolites in the enterocytes via active efflux unto the intestinal lumen

Question 8

what is the P-gp and CYP3A4 relationship?

Answer 8

• causes recirculation of the drug
• increases the exposure to CYP3A4
• generally leads to lower bioavailabilty
• inter-indivudual variability in drug absorption and bioavailabilty

Question 9

what are the rate limiting steps in drug absorption?

Answer 9

Movement of drug across membrane may be rate limited by either
• Perfusion - membrane is not a barrier so it can pass through very easily. Rapid movement through membrane
• Permeability - barrier is produced through the membrane

Question 10

what is perfusion rate limitation?

Answer 10

 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 11

what is permability limited absorption?

Answer 11

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 12

what is release or dissolution rate limited absorption?

Answer 12

 Modified/controlled release formulations – MR, CR
 Adjusted rate of release from the formulation
 Affects the absorption and plasma concentration-time profile of a drug
 Different dosing interval compared to immediate release formulations

Question 13

does the permeability of the 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
 Rate limitation to begin with is the release of the drug and then after this there is no issues as it is a permeable membrane. But as you move to distal region the poor permeability is the rate limitation there is a shift.

Question 14

what are the implication of intestinal first pass/

Answer 14

 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
 Absorption site – intestinal lume

Question 15

what are irreverisble inhibirors which can cause a clinical drug-drug or drug-food interaction?

Answer 15

 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
  plasma concentrations of the ‘victim’ drug
 Recommended NOT to be taken with some statins

Question 16

what are the effects of grapefruit juice on simvastatin/

Answer 16

• Simvastatin – F<5%, extensive first-pass metabolism (intestine and liver)
• Grapefruit juice Cmax and AUC of simvastatin
• Leads to  risk of adverse effects of simvastatin

Question 17

what are examples of drugs with low oral bioavailabilty due to extensive first pass?

Answer 17

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

Question 18

what factors affect bioavailabiluty?

Answer 18

 Incomplete absorption – F
 Low intestinal permeability of large polar molecules (vancomycin)
 Poor dissolution (sparingly soluble drugs)
 Extensive first-pass metabolism in the intestine and liver - F
 Inhibition of hepatic or intestinal first-pass - 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 – F or F
 coeliac disease, liver cirrhosis (mainly CYP3A substrates

Question 19

what is intramuscular /subcut absorption?

Answer 19

 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 20

what is pulmonary absorption?

Answer 20

 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