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Drug interactions

Q: What is the case if the extraction ratio is low? (< 0.3)

This means that the metabolic clearance is smaller than 400 ml/min. The hepatic clearance is determined by enzyme activity and plasma protein binding. The hepatic blood flow is not limiting (so it does not affect the clearance) This is the case in 1) low enzyme activity, 2) high plasma protein binding. It applies for most drugs and usually F has a low variabililty but a high value (approaching 1) An example is diazepam (cl = 1,3=0,4 ml/kg/min = 20-30 ml.min, F = 98%)

5 important questions on Drug interactions

What is a bidirectional interaction?

e.g. phenobarbital inhibits the absorption of furosemide. But the renal clearance of phenobarbital is increased by the diuresis produced by furosemide.

What is mechanism-based inhibition?

This is an inhibition based on the forming of a metabolite that effectively covalently binds to the enzyme and therefore inhibits it.

What is the hepatic clearance?

This is the volume of blood cleared by the drug per unit of time by biotransformation or excretion into bile (feces).
It is determined by:
- enzyme activity (intrinsic clearance (define by Vmax, Km))
- plasma protein binding (fraction unbound (fu= cu/ctotal)
- hepatic blood flow (normal value 1350 ml/min). (This is 25% of cardiac output)

What is the extraction ratio?

It is the fraction of unbound drug that is removed from the blood during the passage of the liver. It is defined as hepatic (blood) clearance divided by the hepatic blood flow. The value is always somehere between 0 and 1.

What is the case if the extraction ratio is low? (< 0.3)

This means that the metabolic clearance is smaller than 400 ml/min.
The hepatic clearance is determined by enzyme activity and plasma protein binding. The hepatic blood flow is not limiting (so it does not affect the clearance)

This is the case in 1) low enzyme activity, 2) high plasma protein binding.
It applies for most drugs and usually F has a low variabililty but a high value (approaching 1)

An example is diazepam (cl = 1,3=0,4 ml/kg/min = 20-30 ml.min, F = 98%)