DRUG TRANSPORTERS IN THE INTESTINE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 498

and/or lymphatic circulation. Therefore, C 2 becomes insignificant. This is known as
sink conditions and serves as the driving force for drug absorption. Passive diffusion
from the intestine is governed by the equation

J = PC 1 (2)

The passive diffusive permeability is defined as

KD
h

P = (3)

where K is the partition coefficient between the aqueous phase and the membrane,
D is the membrane diffusion coefficient (or membrane diffusivity), and h is the
membrane thickness. It is very difficult to calculate a P value using this equation
under physiological conditions because the determination of K , D ,or h is difficult.
Practically, permeability can be measured using the equation

dM
dt

1
SC 1

P = (4)

where dM/dt is the slope of a linear region of transported mass versus time S is the
surface area of membrane where transport takes place and C 1 is the concentration on
the intestinal luminal side (also known as the donor side).
Numerous drug-transporting membrane proteins have been identified in the in-
testinal tissues of humans and various laboratory animal species. While the detailed
working mechanisms of most transporters remains unclear to us at this time, it has
been deduced and demonstrated experimentally that carrier-mediated drug transport is
concentration dependent and saturable. Therefore, transporter-facilitated (i.e., carrier-
mediated) drug transport is described by the following form of the Michaelis-Menton
equation :

J max C
K m +

J c = (5)

C

where J c is transporter-facilitated drug flux, J max is the maximal drug flux, K m is the
Michaelis constant (or drug-transporter affinity constant), and C is drug concentration.
In a manner similar to enzymatic degradation reactions, transporter-facilitated drug
flux can also be inhibited by other compounds in a competitive or noncompetitive
manner. The equations governing these two types of inhibitions follow, and their
derivations, are similar to typical enzymatic reaction equations.
Competitive inhibition:

J max C

J c = (6)

K m (1 + 1 / K i ) + C