Question 20

College Answer

Most candidates structured their answer to this question well – they were aware of first pass metabolism and the effect of protein synthesis upon volume of distribution of drugs. Knowledge concerning Phase I and Phase II reactions was frequently inadequate. Many candidates were aware that these processes as well as inactivating or activating drugs resulted in increased water solubility to aid excretion via bile or urine. Few candidates discussed the significance of the large blood flow to the liver or the implications of high and low extraction ratios especially in relation to liver blood flow.

Discussion

To include all the expected points, this answer could be structured by splitting the content into three major categories. These could be the clearance functions of the liver, first pass metabolism, mechanisms of hepatic metabolism, and the effects of liver disease.

The role of the liver in drug clearance:

• The role of the liver in pharmacokinetics is as an organ of clearance.
•  The two major determinants of hepatic clearance are the efficiency of drug removal from the blood and the efficiency of blood delivery to the liver.
• Efficiency of drug removal by the liver is described by the hepatic extraction ratio, which is the fraction of the drug entering the liver in the blood which is irreversibly removed (extracted) during one pass of the blood through the liver.
• The hepatic extraction ratio is determined largely by the free (unbound) fraction of the drug and by the intrinsic clearance rate, which is the intrinsic ability of the liver to remove (metabolise) the drug in absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding.
• The effect of liver blood flow on hepatic clearance depends on the hepatic extraction ratio of the drug.
• With increasing hepatic blood flow, hepatic extration ratio will decrease for all drugs.
• For drugs with low intrinsic clearance:
  • Hepatic extraction ratio will drop more rapidly with increasing hepatic blood flow
  • Hepatic clearance will not increase significantly with increasing blood flow
• For drugs with high intrinsic clearance:
  • Hepatic clearance will increase in a fairly linear fashion, in proportion to hepatic blood flow
  • Increasing the intrinsic clearance will have diminishing effect on total hepatic clearance 

The effect of the liver on first pass metabolism:

• First pass clearance is not just hepatic but is a combination of metabolism by gut bacteria, metabolism by intestinal brush border enzymes, metabolism in the portal blood and metabolism by liver enzymes.
• For drugs with low hepatic extraction ratio:
  • First pass clearance will be low
  • A change in liver enzyme activity will lead to a proportional change in first pass metabolism, which may not change the bioavailability by a clinically significant degree.
• For drugs with high hepatic extraction ratio:
  • First pass clearance will be high
  • A small change in liver enzyme activity will lead to only a small change in first pass metabolism, but a large clinically significant change in bioavailability

Biotransformation in the liver

• By convention, the metabolic functions of the liver are divided into Phase I and Phase II reactions
  • Examples of Phase I reactions:
    • Hydrolysis
    • Reduction
    • Oxidation.
  • Characteristics of Phase I reactions:
    • these reactions expose or introduce a functional group (–OH, –NH2, – SH or –COOH)
    • They usually result in a small increase in hydrophilicity.
  • Examples of Phase II reactions:
    • Glucouronidation
    • Sulfation
    • Acetylation
    • Methylation
    • Conjugation with glutathione
    • Conjugation with amino acids eg. taurine, glutamine, glycine
  • Characteristics of Phase II reactions:
    • The products are supposed to be significantly more hydrophilic than the original substrate

Effects of changes in liver function

• The effects of changes in synthetic function
  • The liver synthesises plasma proteins; plasma protein binding influences the volume of distribution
  • Low plasma protein levels lead to raised free drug levels (the free fraction increases)
  • This process is therefore synergistic with the concurrent decrease in liver blood flow and hepatic extraction ratio
  • The liver synthesises plasma esterases and peptidases; these metabolise certaindrugs
  • Significant liver disease can result in prolonged clearance of drugs which are susceptible to these enzymes (eg. suxamethonium)
• The effect of changes in secretory function
  • Drugs and metabolites which rely on biliary excretion will be retained, and may require dose adjustment
  • Drugs which enjoy enterohepatic recirculation may have decreased halflives due to failure of recirculation
  • High bilirubin levels may result in the displacement of drugs from albumin as it competes for binding sites 
  • Decreased secretion of bile may result in malabsorption 
• The effects of portal hypertension on pharmacokinetics
  • Portal venous hypertension leads to shunting of portal venous blood into the systemic circulation
  • This has the effect of decreasing first pass metabolism

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