RT Journal Article
SR Electronic
T1 Process and System Clearances in Pharmacokinetic Models: Our Basic Clearance Concepts Are Correct
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 532
OP 542
DO 10.1124/dmd.122.001060
VO 51
IS 4
A1 Ken Korzekwa
A1 Swati Nagar
YR 2023
UL http://dmd.aspetjournals.org/content/51/4/532.abstract
AB 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.SIGNIFICANCE STATEMENT There are two basic kinds of clearances used in pharmacokinetic models, process and system clearances. We show that organ and systemic clearances are net clearances with blood or plasma as the driving concentration. For linear pharmacokinetics, clearance is constant for elimination from the central compartment but varies with time for peripheral elimination. Despite the different kinds of clearance parameters and models, standard clearance models and concepts remain valid.