PK 08: Clearance – The Well-Stirred Model

Question 1

What is the well-stirred model?

Answer 1

theoretical model used to estimate organ-specific clearance

Question 2

What is fu?

Answer 2

fraction of unbound drug in plasma/blood

• assume fu,p ~ fu,b

Question 3

What is CL intrinsic?

Answer 3

innate ability of enzymes or transporters located within the organ to remove drug (without limitations of binding or blood flow)

Question 4

What does the well-stirred model assume?

Answer 4

the drug is distributed instantly and homogenously throughout the organ (ie. liver) and perfusing blood (ie. no permeability limitations)

Question 5

What is the major limitation of the well-stirred model (what does it NOT account for)?

Answer 5

the influence of drug permeability on organ clearance

• for drug with permeability-limited distribution (↑ MW, ↓ LogP), transport of drug across tissue membranes (endothelial, cellular, or both) can limit clearance – which violates the ‘well-stirred’ assumption of the model
• CL_H is sensitive to changes in P x SA (and less sensitive to changes in CL_int, Q_H, or fu)

Question 6

Describe the power of the well-stirred model.

Answer 6

if you know the drug’s E, the well-stirred model can determine HOW and WHY drug PK changes in patients with different physiology

• this is the basis of why different patients require different doses

Question 7

What are the 4 factors that influence organ clearance?

Answer 7

• blood flow
• binding in plasma/blood
• intrinsic clearance
• permeability

Question 8

What is the hepatic extraction ratio (E_H) for a high E drug?

Answer 8

> 0.7

• efficiently removed by the liver
• relatively insensitive to changes in any parameter

Question 9

What is the hepatic bioavailability (F_H) of a high E drug?

Answer 9

low (closer to 0)

• sensitive to changes in all parameters

Question 10

What is the hepatic extraction ratio (E) for a low E drug?

Answer 10

< 0.3

• poorly removed by the liver
• sensitive to changes in all parameters

Question 11

What is the hepatic bioavailability (F_H) of a low E drug?

Answer 11

high (closer to 1)

• relatively insensitive to changes in any parameters

Question 12

What is the extraction ratio for a moderate E drug?

Answer 12

0.3-0.7

Question 13

Can you simplify the well-stirred model equations for moderate E drugs?

Answer 13

NO

• CL, E, and F are sensitive to all parameters (Q_H, fu, CL_int)