Journal o f Pharmacokinetics and Biopharmaceutics, Vol. 1, No.

2, 1973

Clearance Concepts in PharmacokineticsX

Malcolm Rowland, 2 Leslie Z. Benet, 2 and Garry G. Graham 2'3

Received Feb~ 23, 1972--Final July 13, 1972

The kinetics of a drug eliminated by first-order processes in a perfusion-limited isolated perfused

organ system are examined. In this model, the mean clearance, determined by dividing the dose by
the area under the blood concentration profile, and the steady-state clearance are shown to be
equal. The perfusion model and the compartmental model are compared and contrasted. Effects
of blood flow and reservoir size on drug clearance are examined. Similarities and differences be-
tween the isolated and the in vivo organ system are explored. The virtue of using clearance, instead
of half-life, as a correlative parameter between these systems is stressed.

KEY W O R D S : drug clearances ; perfusion models ; isolated perfused organ systems ; p h a r m a -

cokinetic clearance ; steady-state clearance.

INTRODUCTION

In a previous publication, the application of clearance concepts to the

determination of the fraction of an oral dose metabolized in the first passage
through the liver was examined (1). It was shown that the clearance cal-
culated by dividing the intravenous dose by the area under the blood con-
centration-time curve is an average value. In pharmacokinetics, for systems
in which elimination proceeds by a first-order process, this average clearance
is assumed to be constant throughout drug elimination and equal to the
clearance of the drug determined at steady state. When experimentally
tested, the equality between the average clearance and that at steady state

Supported by G r a n t N I G M S 16496 from the National Institutes of Health, U.S. Public Health
Service, Bethesda, Maryland.
This paper was submitted to a Consulting Editor who served as the Journal Editor during its
review process.
z Department of Pharmacy, University of California, School of Pharmacy, San Francisco,
California 94122.
3 Present address : Riker M M M Laboratories, Sydney, N.S.W., Australia.
123

9 1973Plenum Publishing Corporation, 227 West 17th Streel, New York, N.Y. 1001l.
124 Rowland, Benet, and Graham

was demonstrated (2). However, attempts at a more rigorous mathematical

proof appear to be lacking in the literature.
These concepts are assuming increased importance with the advent of
a number of pharmacokinetic studies involving the use of isolated perfused
organ systems. Von Bahr et al. (3) noted that the half-lives of antipyrine,
oxotremorine, and phenylbutazone, compounds which have small volumes
of distribution in vivo, agree closely with those half-lives determined in the
in vitro perfused liver preparation. However, those drugs having large in
vivo volumes of distribution exhibited in vitro half-lives which were only
2-7 ~o of the half-lives seen for these drugs in vivo. This striking difference
should be and indeed is found to diminish when the in vivo and in vitro
clearances of each drug are correlated (4), since the latter parameter should
not be influenced by the distribution of drug outside the eliminating organ.
The present paper examines the kinetics of a drug in a perfused organ system
and compares this perfusion model with the corresponding linear two-
compartment open model. Bischoff and Dedrick (5) have extensively dealt
with the general properties of this compartmental model and have con-
sidered the influence of organ flow and plasma and tissue binding in their
treatment. These workers developed dimensionless solutions for this model
which either allow prediction of the concentration function in a compart-
ment when the model parameters are known or assist in parameter esti-
mation from an experimental plasma concentration-time curve. The present
paper supplements the treatment of Bischoff and Dedrick by discussing the
concept of clearance, its relation to organ blood flow, and its application to
pharmacokinetics.

INTRAVENOUS CLEARANCE
Diagrammatically, the isolated perfused organ system may be depicted
as in Fig. 1. In this model, it is assumed that distribution into the eliminating
organ is perfusion rate limited such that drug in this organ is in equilibrium
with that in the emergent venous blood. It is also assumed that the con-
centration of drug in blood entering the organ equals that in the reservoir,
and similarly concentrations in blood leaving the organ and entering the
reserveir are equal. Similar assumptions are made by Bischoff and co-
workers in perfusion models describing thiopental (6) and methotrexate
pharmacokinetics (7). If, for example, the eliminating organ is the liver,
elimination can occur by metabolism or biliary excretion and is assumed to
be a first-order process.
Let a bolus of drug be introduced into the reservoir, yielding an initial
concentration C ~ Since a mass balance across the reservoir and the elim-