Question 15

College Answer

Clearance was generally well answered.

It is the volume of plasma cleared of a drug per unit time, not the mass of drug cleared. An equation was helpful in identifying the relevant components of hepatic clearance.

Cl_Hep=Q_H X ER_Hep ER_Hep= FU x Cl_Int / Q_H + FU x Cl_Int

Q_H = hepatic blood flow

ER_Hep = hepatic extraction ratio

FU = fraction of drug unbound in plasma

Cl_Int = hepatic enzymatic capacity

Many candidates did not describe the effects of hepatic blood flow and intrinsic clearance on drugs with high and low hepatic extraction ratios. Some discussion of Phase I and II reactions was also expected.

Discussion

Definition of clearance (Birkett, 2009):

"Clearance" describes the efficiency of irreversible elimination of a drug from the systemic circulation.  Clearance is defined as 'the volume of blood cleared of drug per unit time'.

Definition of hepatic extraction ratio (Birkett, 2009): 

"Hepatic extraction ratio ... 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".

Where:

Q_H = hepatic blood flow

E_H = hepatic extraction ratio

fu = fraction of drug unbound in plasma

Cl_Int = hepatic enzymatic capacity

Role of the liver in drug clearance:

• The two major determinants of hepatic clearance are hepatic extraction ratio and hepatic blood flow
• Hepatic extraction ratio 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
• Intrinsic clearance is the intrinsic ability of the liver to remove (metabolise) the drug in the 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 

Some discussion of Phase I and Phase II reactions:

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

Rowland, Malcolm, Leslie Z. Benet, and Garry G. Graham. "Clearance concepts in pharmacokinetics." Journal of pharmacokinetics and biopharmaceutics 1.2 (1973): 123-136.

Wilkinson, Grant R., and David G. Shand. "A physiological approach to hepatic drug clearance." Clinical Pharmacology & Therapeutics 18.4 (1975): 377-390.

McKindley, David S., Scott Hanes, and Bradley A. Boucher. "Hepatic drug metabolism in critical illness." Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy 18.4 (1998): 759-778.

Rowland, Malcolm, Leslie Z. Benet, and Garry G. Graham. "Clearance concepts in pharmacokinetics." Journal of pharmacokinetics and biopharmaceutics 1.2 (1973): 123-136.

Brauer, Ralph W. "Liver circulation and function." Physiological reviews 43.1 (1963): 115-214.

AHMAD, ANIS B., PETER N. BENNETT, and MALCOLM ROWLAND. "Models of hepatic drug clearance: discrimination between the ‘well stirred’and ‘parallel‐tube’models." Journal of Pharmacy and Pharmacology 35.4 (1983): 219-224.