Integration new

Question 1

Average PK parameters for warfarin and a 70 kg patient: 
Total clearance, Cltotal = 0.2 L/h 
Free fraction, α = 0.005 
Volume of distribution = 11 L 
Hepatic blood flow, QH = 90 L/h

Should warfarin be considered a drug with a high or low hepatic extraction ratio? Justify.

Answer 1

EH = ClH/QH
EH = 0.2/90
EH = 0.002L --> 2.2mL of the 90L/h entering the liver is cleared. 

Therefore it has a low extraction ratio.

Question 2

For a low EH drug what will be the effect of a drug that is an enzyme inducer on the following:
Intrinsic clearance
Clearance
V
Css

Answer 2

V: unchanged as it does not affect the free fraction (alpha) of the low EH drug.

Intrinsic clearance: Increased. Low EH means that Cl(H) = free fraction (alpha) x Cl (intrinsic).

Clearance: Low EH means that Cl(H) = free fraction (alpha) x Cl (intrinsic).

Css

Question 3

For a drug with low EH, Cl(H) depends on what?

Answer 3

Cl(H) = free fraction (alpha) x Cl (intrinsic)

Question 4

Any EH value lower than what is considered to represent low hepatic extraction ratio?

Answer 4

Lower than 30%

Question 5

What does accumulation depend on?

Answer 5

The relative value of tau (dosing) interval with respect to the half life of the drug. Patients with liver disease will have reduced Clint which will result in a decreased Cl for a drug with low EH and consequently longer half-lives and increased accumulation. `

Question 6

How does the Cl relate to the Dose and the AUC(iv)?

Answer 6

Cl = D/AUC(iv)

Question 7

How does F relate to AUC(oral) and AUC(iv)?

Answer 7

F = AUC(oral)/AUC(iv)