Define clearance and hepatic extraction ratio (30% of marks). Describe the role of the liver in drug clearance with examples (70% of marks)
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.
ClHep=QH X ERHep ERHep= FU x ClInt / QH + FU x ClInt
QH = hepatic blood flow
ERHep = hepatic extraction ratio
FU = fraction of drug unbound in plasma
ClInt = 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.
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:
QH = hepatic blood flow
EH = hepatic extraction ratio
fu = fraction of drug unbound in plasma
ClInt = hepatic enzymatic capacity
Role of the liver in drug clearance:
Some discussion of Phase I and Phase II reactions:
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.