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RNSH 2003 Pharm
Question 4
Diazepam is a drug metabolised by the liver. Hepatic extraction ratio 0.9, hepatic
clearance 100L/min. What is the reason for increased serum levels in cirrhosis?
(a) reduced protein binding
(b) increased bioavailability
(c) reduced hepatic clearance
(d)
(e)
Hepatic extraction ratio – fraction of the drug entering the liver in the blood which
is irreversibly removed during first pass of blood thru the liver.
Extraction ratio can range from 0 (no drug removed) to 1.0 (all drug removed on
first pass).
Clearance of a drug by the liver will depend on the hepatic blood flow and on the
efficiency of removal of drug presented to it (extraction ratio).
Hepatic clearance = hepatic blood flow X hepatic extraction ratio
Usually only drug which is free and unbound in the plasma is available for
extraction by the liver, except in drugs with very high extraction ratio when bound
and unbound drugs can be metabolised on first pass.
High hepatic extraction ratio drugs
Diazepam is a drug with a high hepatic extraction ratio (according to the
question, but in reality it has a low hepatic extraction ratio!)
Most of the drug is extracted on first pass through the liver. Inducing or inhibiting
the metabolizing enzymes has only a small effect on hepatic extraction ratio, but
has a major effect on the proportion escaping extraction (1-hepatic extraction
ratio) and thus a major effect on bioavailability
Hepatic systemic clearance is determined by hepatic blood flow, thus changed in
the blood flow will have a huge impact on the first pass metabolism.
Low hepatic extraction ratio drugs
Hepatic clearance is only determined by protein binding and enzyme activity.
Hepatic blood flow has little impact.
Thus answer for the figures given in the question would be (c)