Process and System Clearances in Pharmacokinetic Models: Our Basic Clearance Concepts Are Correct

Abstract

Clearances are important parameters in pharmacokinetic (PK) models. All clearances in PK models are either process clearances that include diffusion, transport, and metabolism clearances or system clearances that include organ and systemic clearance. Clearance and volume of distribution are two independent parameters that characterize drug disposition in both individual compartments and systems of compartments. In this minireview, we show that systemic and organ clearances are net clearances that can be easily derived by partition analysis. When drugs are eliminated from the central compartment by first-order processes, systemic clearance is constant. When drugs are eliminated from a peripheral compartment, instantaneous systemic clearance will vary with time. However, average clearance and clearance at steady state will be constant and will equal dose divided by area under the curve. We show that peripheral elimination will not have a large impact on most pharmacokinetic analyses and that standard models of organ and systemic clearance are useful and appropriate.