L37 - Metabolism 2

• Define Hepatic Extraction Ratio

  - The fraction of the drug which enters the liver and is eliminated.

  
  

  - Ratio between hepatic elimination rate and rate of presentation of drug to liver.

  
  

  - Measure of liver efficiency in eliminating the drug from systemic circulation over a single pass through the organ.

  
• What's the eqn for rate of presentation?

  Rate of presentation= Blood flow into liver - [drug] entering liver

  = Qh x Centering

  
• Give the eqn for rate of elimination in the liver.


  Rate of elimination= blood flow into liver X difference in [drug] entering and leaving

  = Qh X (Centering - Cleaving.

  
• Give the eqn for Hepatic Extraction Ratio


  Eh = rate elimination / rate presentation.

  
  

  = Qh x (Centering - Cleaving) / Qh x Centering

  
• Describe what it means if hepatic extraction ratio = 0.

  
  

  If E = 1?

  If E = 0, drug is NOT eliminated. Centering = Cleaving.

  
  

  
  

  If E = 1, then all the drug is eliminated.

  
  

  So if E = 0.25, 25% of the drug entering the liver is eliminated.
• Define Hepatic Clearance.

  
  

  What does it measure?

  ClH = volume of blood entering the liver from which all drug is removed per unit time.

  
  

  = ratio between hepatic elimination rate and incoming concentration.

  
• Give the equation for hepatic clearance.

  ClH = elimination rate / Centering.

  
  

  ClH = Qh x Eh

  
• When can it be said that most of the drug being delivered is removed by the liver?

  If it's a short time required for the drug to:

  
  

  - leave blood cells.

  
  

  - dissociate from plams proteins.

  
  

  - diffuse across hepatic membranes.

  
  

  - be metabolised by enzymes.

  
  

  - be transported to bile.

  
• If most of the drug being delivered to the liver is removed, what does it mean for extraction ratio?

  
  

  What about hepatic clearance?

  Extraction ratio is high and approaches 1. Eg, could be <0.7.

  
  

  Hepatic clearance approaches blood flow.

  
• What's the eqn for hepatic clearance?

  ClH = extraction ratio x blood flow

  
• What are some values that describe a high hepatic extraction ratio?

  
  

  What limits clearance?

  0.7-1.

  
  

  - Clearance is perfusion rate limited.

  
  

  - Elimination process depends on the blood bringing more drug.

  
  

  - Requires fast dissociation from plasma proteins, passage through the membranes and into bile.
• Hepatic Clearance of drugs with a HIGH hepatic extraction ratio....

  
  

  Are they sensitive to blood flow changes? Changes in plasma binding?


  - Very sensitive to blood flow changes.

  
  

  - Sensitive to changes in plasma binding/enzymatic interactions.

  
  

  - Low systematic absorption: metabolised by Hepatic first pass.

  
• Why might drugs have a smaller hepatic extraction ratio?

  
  

  What values count as low E?


  - Slower dissociation from erythrocytes/plasma proteins.

  
  

  - Slow diffusion into hepatocytes.

  
  

  - Slow enzymatic reactions (most frequent reason!).

  
  

  - Slow transport into bile.

  
  

  E = <0.3
• What factors limit hepatic elimination?

  - Partitioning out from blood cells.

  
  

  - Dissociation from plasma proteins.

  
  

  - Passage through membranes/into bile ducts.

  
  

  - Drug is a poor substrate for the enzyme (most frequent).
• Hepatic Clearance of drugs with a LOW hepatic extraction ratio....

  
  

  Are they sensitive to blood flow changes? Changes in plasma binding?


  - Insensitive to blood flow changes.

  
  

  - Sensitive to blood flow changes/changes in plasma binding/enzymatic interactions.