First Pass and Bioavailability

Question 1

Equation for bioavailability?

Answer 1

F = Fa Fg Fh

Fa = fraction absorbed
Fg = fraction escaping intestinal metabolism
Fh = fraction escaping hepatic metabolism

Question 2

Implications of intestinal first pass?

Answer 2

• limits value of the oral route (low Fg due to metabolism in enterocytes)
• significant contributor to low and variable F for many oral drugs e.g. statins, HIV protease inhibitors
• can be worsened by transporter interplay

Question 3

How can first pass metabolism lead to DDIs?

Answer 3

If metabolic enzymes are blocked by drugs, it can increase levels of other drugs which are usually significantly metabolised in the first pass, leading to toxicity

Question 4

Effects of food on intestinal first pass?

Answer 4

• CYP3A4 is the most abundant P450 enzyme
• grapefruit juice selectively inhibits intestinal CYP3A4 irreversibly
• co-administration of grapefruit juice and CYP3A4 substrate (e.g. statin) can lead to increased plasma levels of the drug, as Fg is higher

Question 5

Effect of grapefruit juice on simvastatin?

Answer 5

Simvastatin has F < 5%, extensively metabolised. Grapefruit juice causes huge icnrease in Cmax and AUC, so much higher risk of adverse effects

Question 6

Effect of formulation on bioavailability?

Answer 6

expression of metabolic enzymes changes along the GIT

• immediate release forms have higher exposure the the enzymes higher in the GIT (duodenum, jejunum) so metabolised more
• modified release don’t release until later on in the tract, ileum has less CYP3A4 and colon has none so less metabolism and more absorbed

Question 7

Factors affecting bioavailability

Answer 7

• incomplete absorption (reduces F) due to permeability or solubility issues
• extensive first pass metabolism
• inhibition of metabolic enzymes in the gut and liver
• competing reactions (enzymatic or non (e.g. complexation))
• effect of surgery and disease (gastric bypass, coeliac, liver cirrhosis)

Question 8

What must be considered for IM and SC administration in terms of absorption?

Answer 8

characteristics of the drug and the membrane

Question 9

Properties of the muscle capillary membrane

Answer 9

different to the gut wall - membrane more porous, drugs more readily absorbed via paracellular route
- absorption is generally perfusion rate limited irrespective of Pka and polarity

Question 10

What usually limits absorption for transdermal administration?

Answer 10

generally permeability rate limited, even for lipophilic compounds (skin is a difficult barrier to cross)

Question 11

Benefits of pulmonary administration?

Answer 11

no first pass metabolism, very well perfused (however 90% of the dose is usually swallowed so low proportion is deposited in the lungs)