INTERPLAY OF DRUG TRANSPORTERS AND ENZYMES ON HEPATIC DRUG PROCESSING - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 711

of the circulation are of paramount importance. The incompleteness of micromixing
of PV and HA and bypass of the HA will affect drug clearance in liver. 23 − 26 If flow
to the region is absent, metabolism and excretion would not occur. Hence, drugs in
the circulation are delivered to the sinusoidal membrane and must recruit transporters
for entry or enter passively before they are acted on by the enzymes intracellularly.
The flow pattern is expected to be more important in the modulation of clearances of
drugs with high hepatic extraction ratios. 27

23.2. MODELS OF HEPATIC DRUG CLEARANCE

The efficiency of hepatic removal is based on clearance concepts. Hepatic clearance
(CL liver , tot ) is the volume of perfusing blood cleared of the drug per unit time. CL liver , tot
is a proportionality constant that equals the rate of elimination divided by the concen-
tration of drug entering the liver and is the product of the hepatic blood flow ( Q ) and
the extraction ratio ( E ). 28 The relationship that CL liver , tot =

QE is simple but mislead-
ing, since E is modulated by common factors such as flow rate, unbound fraction, the
enzymes, and transporters.
Various hepatic clearance models have been developed to elucidate the removal
mechanisms and predict drug extraction in the liver. Two conventionally used models
are the well-stirred model , which views the liver as a well-stirred compartment with
concentration of drug in the liver in equilibrium with that in the emergent blood,
and the parallel tube model , which regards the liver as a series of parallel tubes with
enzymes distributed evenly around the tubes, with the concentration of drug declin-
ing along the length of the tube. 27 − 31 These models reflect extreme flow conditions
of complete and rapid mixing (well-stirred model) or lack of mixing (parallel tube
model) (Figure 23.2). The reality is an intermediate degree of mixing, the dispersion

Flow pattern

(a)

(b)

(c)

PP PV

FIGURE 23.2. Hepatic clearance models based on flow patterns: ( a ) bulk flow, infinite mixing:
well-stirred model (dispersion number D N =∞ ); ( b ) plug flow, no mixing: parallel tube model
( D N = 0); ( c ) dispersion flow, intermediate mixing: dispersion model ( D N > 0).