ACATPlus™

ACATPlus™ extends the classic ACAT model to include extra colon segments and gut wall tissue. For human subjects, the ACATPlus™ model incorporates ascending, transverse, descending, and sigmoid colon and rectum regions. For mouse and rats, the whole colon has been divided into Colon 1, Colon 2, Colon 3, and Colon 4. For dogs, the whole colon has been divided to Ascending Colon, Transverse Colon, Descending Colon 1, and Descending Colon 2.

Physiology parameters in ACATPlus™

Table 1-4: PH parameters in GastroPlus® for GIT segments along with the addition of extended colon segments in mouse, rat, dog, and human (Fasted State)

Table 1-5: Transit time parameters in GastroPlus® for GIT segments along with the addition of extended colon segments in mouse, rat, dog, and human (Fasted State)

Table 1-6: Radius parameters in GastroPlus® for GIT segments along with the addition of extended colon segments in mouse, rat, dog, and human

Table 1-7: Length parameters in GastroPlus® for GIT segments along with the addition of extended colon segments in mouse, rat, dog, and human

Table 1-8: Water concentration in intestinal content in mouse, rat, dog, and human

Gut Tissue Model

Each segment in ACATPlus™ incorporates multiple tissue compartments: mucus, enterocyte, mucosa, sub-mucosa, and muscularis propria, as shown in Figure 1-10.

Figure 1-10: Gut Tissue Model

In the ACATPlus™ model, the mucus layer has been divided into multiple sublayers to describe the distribution delay from the lumen to the top of the enterocyte caused by diffusivity and binding in the mucus layer.

Mass transport model in mucus layer

The ACATPlus™ model divides the mucus layer to 20 sublayers. The mass transport model in the mucus layer incorporates the following mechanisms: generation of new mucus from goblet cells in gut epithelium, shedding off the mucus from the top sublayer, and the diffusion process, as shown in Figure 1-11.

Figure 1-11: Mass Transport model in Mucus Layer

Equation 1-64: The diffusion process from sublayer i to sublayer i+1

where:

Equation 1-65: Mucus regeneration rate incorporated in the calculation of mucus turn over time

Mucus regeneration will cause compound transit from sublayer i to sublayer i-1. The corresponding transit rate has been defined as MucusTurnOverRate. MucusTurnOverRate from the first sublayer represents the shedding off rate, which will transport the compound from mucus to lumen.

Equation 1-66: Mucus Turnover Rate in each Sublayer

where:

Equation 1-67: The mass balance in each sublayer

Mass transport model in mucosa, sub-mucosa, and muscularis propria

The mass transport from the enterocyte to the mucosa sub-compartment occurs through the basolateral membrane of the enterocyte. This process includes both transcellular and paracellular diffusion, as well as transportation via transporters, following the same mechanism as the classic ACAT model. The following equations represent the mass balance equations in mucosa, sub-mucosa, and muscularis propria.

Equation 1-68: Mass Transport Model in Mucosa, Sub-Mucosa, and Muscularis Propria

Where:

Equation 1-69: Transcellular and Paracellular Diffusion in Mucosa and Sub-Mucosa

Where P₁₂ and P₂₃ are the permeability coefficients. SA₁₂ and SA₂₃ are the surface area.