L7 - Hepatic Clearance Concepts II

Question 1

Name the 3 factors that determine the hepatic blood clearance of a drug.

Answer 1

1. Hepatic blood flow (Qh)
2. Fraction unbound in blood (fub) protein and blood cell binding
3. Hepatocellular activity (CLint) metabolism and biliary excretion

Question 2

Qh, fu and CLint all have an effect on plasma CL.

Answer 2

False, only fu and CLint do.

Question 3

What are some characteristics of drugs with high hepatic extraction ratio (Eh>0.7)

Answer 3

Eh approaches 1.0, CLb, h will approach Qh.

Drug will have high efficiency in:

• partitioning out of blood cells
• dissociating from plasma proteins
• permeation through hepatic membranes
• metabolism by hepatic enzymes
• biliary excretion into bile.

Elimination will become rate-limited by perfusion.

Clearance is sensitive to changes in blood flow (Qh) but relatively insensitive to changes in plasma protein binding or hepatocellular eliminating activity.

Question 4

What are some characteristics of drugs with low hepatic extraction ratio (Eh<0.3)?

Answer 4

Eh approaches 0, Cin(Ca) and Cout(Cv) are virtually identical.

CLb, h not affected by Qh.

Most common reasons are that the drug:

1. is a poor substrate for the elimination process
2. is polar and has insufficient lipophilicity to permeate readily into the hepatocytes.
3. is substrate of efflux transporter along the sinusoidal (basolateral) membrane.

Clearance is insensitive to changes in blood flow (Qh) but relatively sensitive to changes in plasma protein binding or hepatocellular eliminating activity.

Question 5

What are the effects of Qh on CLb for drugs with different hepatic extraction ratio (graphically)?

Answer 5

High Eh drugs (e.g. lidocaine): increase in hepatic perfusate flow will bring about a proportional increase in clearance.

Moderate Eh drugs (e.g. colloidal chronic phosphate): as hepatic perfusate flow increases, clearance increases at a decreasing rate - may eventually plateau.

Low Eh drugs (e.g. antipyrine): clearance is not affected by hepatic perfusate flow.

Question 6

How would you describe the plasma protein binding for drugs with high Eh?

Answer 6

• liver is capable of removing all the drug presented to it.
• CLb and Eh are minimally affected by the changes in fu.

Question 7

How will you describe the plasma protein binding for drugs with low Eh?

Answer 7

• hepatic clearance depends very much on fu.
• this is because only unbound drug permeates the hepatocytes for elimination.
• unbound drug leaving liver is identical to that entering liver.

Question 8

How do you calculate the hepatic blood clearance for a given drug?

Answer 8

CLb, h = Qh x Eh = CLint x fub

Question 9

How can you calculate fub?

Answer 9

fub = C/Cb x fu x (1-H) 
fub = CLb/CLint

Question 10

What can the well-stirred model be used for?

Answer 10

• to summarise the earlier principles

- to predict the expected direction of change in terms of CLb,h or Eh.

Question 11

What are some assumptions that come with the well-stirred model?

Answer 11

• pulsed input into liver
• complete mixing within liver and elimination
• concentration in sinusoid = output concentration
• exponential decline in output over time
• no diffusion delay
• no active absorption

Question 12

What is the equation for the extended hepatic clearance model?

Answer 12

CLb,h = Qh x Eh = Qh x {(fub.CLinflux.CLint)/[CLefflux.Qh+CLint(Qh + fub. CLinflux)}

Question 13

If fub x CLint &laquo_space;Qh, what is the CLb,h?

Answer 13

CLb,h = Qh x Eh = fub x CLint

Question 14

If fub x CLint&raquo_space;Qh, what is the CLb, h?

Answer 14

CLb,h = Qh x Eh = Qh

Question 15

How would you describe enterohepatic recycling?

Answer 15

• component of redistribution
• applies to drugs, metabolites, glucoronide, conjugates.
• active transportation:
  » polarity
  » molecular weight (>350g/mol)
  » specific transport mechanisms - anionic, cations, neutral organic compounds
• hepatic disease (decrease biliary excretion)

Question 16

How will you calculate biliary clearance?

Answer 16

biliary clearance = [(bile flow x concentration in bile)/concentration in plasma]

Question 17

What are the characteristics of drug that concentrates in bile?

Answer 17

• relatively high biliary clearance (bile-to-plasma concentration ratio can approach 1000)

Question 18

How to calculate total hepatic clearance ?

Answer 18

CLh = CLh,m + CLh, biliary

Question 19

Bile is a product of filtration (T/F).

Answer 19

False, it is the secretion of bile acids and other solutes.

Question 20

There will always be space for biliary transport (T/F).

Answer 20

false, can be saturated and competitively inhibited.