Computer- aided biopharmaceutical characterization: gastrointestinal absorption simulation - Computer-Aided Applications in Pharmaceutical Technology - page 180

6.2 Theoretical background

Simulation software packages, such as GastroPlus™, are advanced
technology computer programs designed to predict PK, and optionally,
pharmacodynamic effects of drugs in humans and certain animals.
The underlying model in GastroPlus™ is the ACAT model (Agoram
et al., 2001), an improved version of the original CAT model described
by Yu and Amidon (1999). This semi-physiological absorption model is
based on the concept of the Biopharmaceutics Classifi cation System
(BCS) (Amidon et al., 1995) and prior knowledge of GI physiology, and
is modeled by a system of coupled linear and nonlinear rate equations
used to simulate the effect of physiological conditions on drug absorption
as it transits through successive GI compartments.
The ACAT model of the human GI tract (Figure 6.1) consists of nine
compartments linked in series, each of them representing a different
segment of the GI tract (stomach, duodenum, two jejunum compartments,
three ileum compartments, caecum, and ascending colon). These
compartments are further subdivided to comprise the drug that is
unreleased, undissolved, dissolved, and absorbed (entered into the
enterocytes). Movement of the drug between each sub-compartment is
described by a series of differential equations. In general, the rate of
change of dissolved drug concentration in each GI compartment depends
on ten processes:

I. transit of drug into the compartment;
II. transit of drug out of the compartment;
III. release of drug from the formulation into the compartment;
IV. dissolution of drug particles;
V. precipitation of drug;
VI. lumenal degradation of drug;
VII. absorption of drug into the enterocytes;
VIII. exsorption of drug from the enterocytes back into the lumen;
IX. absorption of drug into portal vein via paracellular pathway; and
X. exsorption of drug from portal vein via paracellular pathway.

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The time scale associated with each of these processes is set by an
adequate rate constant. Transfer rate constant (k t ), associated with
lumenal transit, is determined from the mean transit time within each
compartment. The dissolution rate constant (k d ) for each compartment at