The ACAT Model

The ACAT model is loosely based on the work of Amidon and Yu who found that seven equal transit time compartments are required to represent the observed cumulative frequency distribution for small intestine transit times [4], Their original compartmental absorption and transit (CAT) model was able to explain the oral plasma concentration profiles of atenolol [21]. 

In spite of its limitations, the ACAT model combined with modeling of saturable processes has become a powerful tool in the study of oral absorption and pharmacokinetics. To our knowledge, it is the only tool that can translate in vitro data from early drug discovery experiments all the way to plasma concentration profiles and nonlinear dose-relationship predictions. As more experimental data become available, we believe that the model will become more comprehensive and its predictive capabilities will be further enhanced. 

Figure 6.4 Schematic of the ACAT model. Reprinted from [176] with permission from Elsevier.

These simple models based on the assumption of a single intestinal compartment have been refined to the advanced compartmental absorption and transport model that allows transit and differential expression of enzymes and transporters down the length of the gastrointestinal tract including pH, fluid, and blood flow differences [3]. The ACAT model is based on a series of integrated differential equations and has been implemented in the commercial software Gastroplus (see Chapter 17). 

We have developed a two-step procedure for the in silico screening of compound libraries based on biopharmaceutical property estimation linked to a mechanistic simulation of GI absorption. The first step involves biopharmaceutical property estimation by application of machine learning procedures to empirical data modeled with a set of molecular descriptors derived from 2D and 3D molecular structures. In silico methods were used to estimate such biopharmaceutical properties as effective human jejunal permeability, cell culture permeability, aqueous solubility, and molecular diffusivity. In the second step, differential equations for the advanced compartmental absorption and transit model were numerically integrated to determine the rate, extent, and approximate GI location of drug liberation (for controlled release), dissolution, and absorption. Figure 17.3 shows the schematic diagram of the ACAT model in which each one of the arrows represents an ordinary differential equation (ODE). 

The form of the ACAT model implemented in GastroPlus describes the release, dissolution, luminal degradation (if any), metabolism, and absorption/exsorption of... 

Simulated HIA% (GastroPlus ACAT model) Figure 17.5 Correlation of experimental and simulated percentage absorbed. Percentage absorbed is defined as the percentage of the dose that crosses the apical membrane of the intestine. Percentage absorbed was simulated using the ACAT model as described in the text. 

Fig. 18.3. ACAT model schematic. The diagram includes the consideration of six states (unreleased, undissolved, dissolved, degraded, metabolized, and absorbed), 18 compartments [nine gastrointestinal (stomach, seven small intestine, and colon) and nine...

The mechanistic simulation ACAT model was modified to account automatically for the change in small intestinal and colon k as a function of the local (pH-dependent) log D of the drug molecule. The rank order of %HIA from GastroPlus was directly compared with rank order experimental %HIA with this correction for the log D of each molecule in each of the pH environments of the small intestine. A significant Spearman rank correlation coefficient for the mechanistic simulation-based method of 0.58 (p < 0.001) was found. The mechanistic simulation produced 71% of %HIA predictions within 25% of the experimental values. 

Table 18.2 lists 30 of the molecules used in this study that are known to be substrates for active transport or active efflux. The mechanistic ACAT model was modified to accommodate saturable uptake and saturable efflux using standard Michaelis-Menten equations. It was assumed that enzymes responsible for active uptake of drug molecules from the lumen and active efflux from the enterocytes to the lumen were homogeneously dispersed within each luminal compartment and each corresponding enterocyte compartment, respectively. Equation (5) is the overall mass balance for drug in the enterocyte compartment lining the intestinal wall. 

GastroPlus [137] and IDEA [138] are absorption-simulation models based on in vitro input data like solubility, Caco-2 permeability and others. They are based on advanced compartmental absorption and transit (ACAT) models in which physicochemical concepts are incorporated. Both approaches were recently compared and are shown to be suitable to predict the rate and extent of human absorption [139]. 

Figure 10.2 Schematic diagram of the advanced compartmental absorption and transit (ACAT) model [18].

The CAT model was further modified to include pH-dependent solubility, dis-solution/precipitation, absorption in the stomach or colon, first-pass metabolism in gut or liver, and degradation in the lumen. Physiological and biochemical factors such as changes in absorption surface area, transporter, and efflux protein densities have also been incorporated. This advanced version of CAT, called ACAT [176], has been formulated in a commercially available simulation software product under the trademark name GastroPlus . A set of differential equations, which is solved by numerical integration, is used to describe the various drug processes of ACAT as depicted in Figure 6.4. 

HMG-CoA reductase, a rate-limiting enzyme of cholesterol synthesis, and ACAT-1, a rate-limiting enzyme of cholesterol esterification, relate to hepatic cholesterol storage. Levels of mRNA of those enzymes were also increased by the lipodystrophy model diet during the onset of hepatic steatosis, but DHA supplementation attenuated this (Fig. 22.6). 

Furthermore, the Pefr data can be integrated with solubility/dissolution data to predict the oral absorption from the solid dosage form (see Chapter 10). Gastrointestinal transit absorption model (GITA) [12, 13], advanced compartmental absorption and transit model (ACAT, GastroPlus), advanced drug absorption and metabolism model (ADAM, SimCYP) and so on have been reported as useful integration models (see Chapter 10). 

Burnett and coworkers have described the synthesis of a very potent class of cholesterol absorption inhibitors (CAI) typified by the original lead compound in this series the compound I showed in Fig. 42 (SCH 48461). This 2-azetidinone has resulted as an effective inhibitor of cholesterol absorption in a cholesterol-fed hamster model [9]. Subsequently, the same molecule has been shown to reduce serum cholesterol in human clinical trials [382]. Although this class of compounds has been initially designed as acyl coenzyme A cholesterol transferases (ACAT) inhibitors, early structure-activity studies demonstrated a striking divergence of in vitro ACAT inhibition and in vivo activity in the cholesterol-fed hamster. A detailed examination of this molecule indicated that the hypocholesterolemic... 

Other lines of evidence also support the notion that deregulated cholesterol homeostasis may contribute to the AD pathogenesis. AD patients have been reported to develop intracellular A/1 accumulation in the late endo-somes and lysosomes. Similar pathological features, including swollen late endosomes and A/ accumulation, have also been reported in Niemann-Pick type C disease patients [52,53], Npcl deficient mice as well as in mouse models of AD [54,55]. The Npcl gene product is essential for the mobihzation of cellular cholesterol. Excess cholesterol can be transported into endoplasmic reticulum and esterified by acyl co enzyme A cholesterol acyltransferase (ACAT) and stored in lipid droplets. Inhibition of ACAT activity has been reported to reduce A/3 levels in vitro and plaque pathology in animal models of AD [56,57]. 

On the basis of the data reviewed in this chapter, it seems likely that there are functionally distinct pools of cholesterol in the intestinal epithelial cell that serve different metabolic functions. These pools are illustrated diagrammatically in the model of an epithelial cell shown in Fig. 14. Pool A is defined as having been derived largely from the uptake of luminal unesterified cholesterol (arrow 1) and serves as a major substrate for the CoA-dependent esterification reaction (arrow 2). The cholesterol esters that result from this reaction are incorporated into the hydro-phobic core of the chylomicron particle. Following cholesterol feeding there is a marked increase in apparent ACAT activity in the intestinal epithelium that seems to be related to an increase in the amount of intracellular cholesterol available to the enzyme under the in vitro conditions of the assay rather than to an increase in the... 

ACAT or a decrease in ACAT activity itself. Because much of the cholesterol accumulating in the cells appears to be associated with lysosomes, it is tempting to speculate that defects in lysosomal cholesterol transport arise in advanced foam cells. In this context, macrophages exposed to oxidized LDL can internalize a substantial amount of cholesterol, but there is relatively little stimulation of ACAT-mediated cholesterol esterification [8]. According to one model, oxysterol-induced inhibition of lysosomal sphingomyelinase leads to accumulation of lysosomal sphingomyelin, which binds cholesterol and thus inhibits transport of the cholesterol out of lysosomes (M. Aviram, 1995). 

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