Is drug clearance a pharmacokinetic constant?

We of course know that the clearance of a drug, regardless of metabolic or renal, may be affected by various environmental and physiologic changes, but from a pharmacokinetic model point of view, we generally regard the Clearance for an individual to be a relative constant,.... as long as the drug 'exhibits linear or first order kinetics'.

In reality, this is only a convenient though fallacious assumption. In reality, Clearance is always concentration dependent. The question is how much, or how little?

Regardless of the processes involved, clearance can be represented by the expression Vmax/(Km+C), where C is the concentration of drug, the Vmax and Km are the rate max and concentration at 0.5Vmax respectively. From the expression it is obvious that Clearance is always concentration dependent. It is only fixed at the extreme ends of the range, where either C = 0, when Clearance becomes the 'intrinsic Clearance', or at the other extreme where concentration is infinitely high.

The maximum concentration-dependence is seen when the concentrations are approximately 0.1Km to 10Km, when there is a 'linear' relationship between Clearance and concentration. This is the range where we empirically label the kinetics as being 'zero-order'. Outside of this range, particularly where the concentrations are less than 0.1Km, the concentration dependance reduces towards a minimum.

So Clearance is always concentration dependent. Most therapeutic drug concentrations are in the range that is fairly low compared to the Km of the elimination processes (or we hope they are), so we comfort ourselves in being able to make the assumption that the drug pharmacokinetic behaviour is consistent with first order kinetics. But this is merely a convenient assumption. Most drugs are likely show various degrees of a mixed first to zero order pharmacokinetic behaviour.

A minority of drugs tend towards an overtly zero order behaviour, e.g. ethanol, omeprazole, phenytoin...... In the next post, we will examine the pharmacokinetic behaviour of one such drug, ethanol.

Visualizing the effects of body weight and clearance on the plasma concentration - time profile

Here is an interactive graph that helps you visualize how the volume of distribution (simplistically affected here by the body weight) and the clearance of a drug affect the plasma concentration - time profile of a drug that is orally administered 3 times a day (8 hourly).

Play around with the sliders provided and see how the profile changes. Note how the half-life changes as well as how the steady state plasma concentrations, area under the curve (AUC), minimum and maximum concentrations change. How about the time required to reach steady state? And how much accumulation occurs under the different situations?

Think about how individual profiles may vary because of differences in body weights and the ability of their bodies to clear specific drugs.

[No canvas support]

BW(kgs): 70       

Clearance: 9.1

Dose Interval = 8hrs,

Accumulation Index: 2.0       Halflife: 8.0