Introduction to PK - Clearance
Hi everyone,
In the last video we made reference to a theoretical concentration at zero-time when the drug is fully in the systemic circulation but before it is subject to elimination. It is theoretical because, once the drug enters the circulation some elimination inevitably takes place.
Drug elimination takes place via a number of key processes.
Metabolism in the liver,
excretion through the kidneys,
and in special situations and it the case of volatiles, through the lungs.
Metabolism can take place anywhere in the body, but the primary organ for metabolism is the liver. And it accomplishes this through two types of enzymatic reactions – oxidative type reactions through a Superfamily of enzymes called Cytochrome P450, and another bunch of unrelated enzymes that conjugate the drug molecule with larger, more water soluble moieties, such as glutathione, glucuronides and sulphates.
How active this process is simply depends on the amount of enzyme expressed in the lliver cells. This in turn may be dependent on body weight, gender, age, genetics and liver disease. Activity of the liver enzymes may also be affected through food and drug interactions.
Excretion occurs primarily through the kidneys, via a number of specific processes aligned along the renal tubules.
Renal elimination is therefore dependent on factors such as glomerular filtration rate, protein binding, expression of specific transporters in the renal tubular cells, …. As well as the number of functioning nephrons. This will be dependent on age and presence of renal disease.
The Clearance of a drug is very simply, the volume of plasma that can be totally cleared of the drug per unit time. And is the sum of what the liver and kidney can respectively do. Since Clearance refers to the amount of plasma that can be cleared per unit time, the Volume of Distribution is important, because it conceptualizes the entire body as being represented by plasma.
In a situation that is not saturated, the clearance of a drug is independent of the drug concentration.
So how does all this affect the pharmacokinetics of a drug? That’s a good question. You can see here, that reducing the clearance increases the concentrations of the drug. Here the half-life in increased.
In a multiple dose situation, you can see that the steady state concentrations increase, and because the half-life increases, the time needed to reach steady-state is correspondingly increased.
That’s all you need to know about clearance for the time being. I know that as we consider more and more of these pharmacokinetic processes, it starts getting confusing. It’s quite normal. I will try and help you put it together in the next video, where we will discuss the integration of concepts.
See you then.