IN VITRO–IN VIVO SCALE-UP OF DRUG TRANSPORT ACTIVITIES - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 559

p -trifluoromethoxyphenylhydrazone (FCCP), rotenone, sodium azide] or at a low
temperature. 5 The methods for determining the quantitative contribution of each trans-
porter to the overall transport are discussed in the following sections.

19.2.2. Rate-Determining Process in Apparent Intrinsic Organ Clearance

Generally, the detoxification process consists of several parts: (1) uptake of com-
pounds from blood to tissue cells, (2) metabolism in an intracellular compartment,
(3) backflux from cells to blood, and (4) excretion from cells into another compart-
ment, such as bile (liver) and urine (kidney). The “apparent” intrinsic organ clearance
(CL int , all ) in such cases can be described as follows:

CL u , metab + CL u , eff

CL int , all =

CL u , influx (2)

(CL u , metab + CL u , eff ) + CL u , back

where CL u , influx ,CL u , metab ,CL u , eff , and CL u , back represent the influx clearance from
blood, metabolic clearance, efflux clearance from cells, and clearance for backflux,
respectively. If (CL u , metab +

CL u , eff ) is much greater than CL u , back , the apparent intrin-
sic clearance is very close to CL u , influx and the influx clearance is solely determined
by the overall intrinsic clearance:

CL int , all ∼

CL u , influx (3)

On the other hand, if (CL u , metab + CL u , eff ) is much lower than CL u , back , the apparent

intrinsic clearance is determined by the activity of all the processes:

CL u , metab + CL u , eff

CL u , back

CL int , all ∼ CL u , influx × (4)

When the membrane transport clearance is very rapid and the membrane transport on
the blood side is symmetric (CL u , influx = CL u , back ), equation (1) can be approximated

by

CL int , all ∼ CL u , metab + CL u , eff (5)

This equation is applicable to lipophilic drugs exhibiting rapid membrane perme-
ability. Considering these equations, the important thing is that even if the major
clearance mechanism of a drug is metabolism, the apparent intrinsic organ clearance
is determined not by metabolic intrinsic clearance but by influx clearance under certain
conditions, as discussed above when a drug is recognized by influx transporters.