The enigmatic AUC (area-under-the-curve)

The area under the plasma concentration-time curve (AUC) is an easily measurable pharmacokinetic parameter. It is used extensively in clinical pharmacokinetic studies, but students very often have a poor idea of what to make of the AUC.

Mathematically, the AUC is obtained by integrating the mathematical function that describes the plasma concentration-time profile. Practically however, it is estimated by summing all the small trapezoids that can be constructed under the concentration-time plot, using what is well known as the "trapezoidal rule".

Since it is mathematically the sum of all the plasma concentrations over the dose interval, it is often taken to represent clinical drug 'exposure'.

Pharmacokinetically however, the AUC is used to estimate drug clearance,

Clearance = Dose/AUC ...................(1)

After an oral dose, the equation is,

Clearance = (Bioavailability x Dose)/AUC ................(2)

A corollary of the above statements is that, since AUC is assumed to represent clinical drug exposure, and since AUC is determined principally by Bioavailability and Clearance, clinical drug exposure can be assumed to be determined primarily by clearance and bioavailability.

This concept has shaped our thinking for many decades, and it has closed our minds to distribution being perhaps an equal if not more important determinant of drug effects (more about this later!).

One particular area of confusion for students is that they too readily associate the AUC with bioavailability. When asked why the AUC changes for a particular drug, their first response is often that the bioavailability has changed. This is only half right.....since the AUC is determined by both clearance and bioavailability. In a situation where there are no bioavailability issues, AUC is determined primarily by clearance. AUC is only reflective of bioavailability when the clearance remains stable.

Experimentally, bioavailability is determined by measuring the AUC under oral and intravenous administrations. The clearance of the drug, measured under intravenous administration allows calculation of the clearance, which can then be used to estimate the bioavailability from the oral experiment.