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

Area of Science:

• Pharmacokinetics
• Drug Disposition
• Quantitative Pharmacology

Background:

• Clearances are critical parameters in pharmacokinetic (PK) models, essential for understanding drug disposition.
• PK models utilize process clearances (diffusion, transport, metabolism) and system clearances (organ, systemic).
• Clearance and volume of distribution are independent parameters characterizing drug behavior in compartmental models.

Purpose of the Study:

• To clarify the nature of systemic and organ clearances as net clearances derivable by partition analysis.
• To examine the behavior of systemic clearance under different elimination scenarios (central vs. peripheral compartments).
• To validate the utility and appropriateness of standard clearance models in pharmacokinetic analyses.

Main Methods:

• Review and analysis of pharmacokinetic models and clearance concepts.
• Partition analysis to derive systemic and organ clearances.
• Comparison of clearance behavior for central versus peripheral elimination pathways.

Main Results:

• Systemic and organ clearances are identified as net clearances, with blood or plasma as the driving concentration.
• For linear pharmacokinetics, clearance is constant when elimination occurs from the central compartment.
• Instantaneous systemic clearance varies with time for peripheral elimination, but average and steady-state clearances remain constant.

Conclusions:

• Peripheral elimination generally has a limited impact on overall pharmacokinetic analyses.
• Standard models and concepts for organ and systemic clearance are deemed useful and appropriate.
• Despite variations in clearance parameters and models, fundamental clearance concepts in pharmacokinetics remain valid.