There is Only One Valid Definition of Clearance: Critical Examination of Clearance Concepts Reveals the Potential for Errors in Clinical Drug Dosing Decisions

Abstract

Drug dosing decisions in clinical medicine and in introducing a drug to market for the past 60 years are based on the pharmacokinetic/clinical pharmacology concept of clearance. We used chemical reaction engineering models to demonstrate the limitations of presently employed clearance measurements based upon systemic blood concentration in reflecting organ clearance. The belief for the last 49 years that in vivo clearance is independent of the mechanistic model for organ clearance is incorrect. There is only one valid definition of clearance. Defining organ clearance solely on the basis of systemic blood concentrations can lead to drug dosing errors when drug effect sites reside either in an eliminating organ exhibiting incremental clearance or in a non-eliminating organ where intraorgan concentration is governed by transporter actions. Attempts to predict clearance are presently hampered by the lack of recognition that what we are trying to predict is a well-stirred model clearance.

Keywords: chemical reaction engineering models; clearance; well-stirred model.

Fig. 1

Chemical engineering reaction (pharmacokinetic) models at steady state (logarithmic concentration on Y-axis)