Enterocyte compartment

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. 

Because the amounts and density of these transporters vary along the gastrointestinal tract, it is necessary to introduce a correction factor for the varying transport rates in the different luminal and enterocyte compartments. Due to the lack of experimental data for the regional distribution, and Michaelis-Menten constants for each drug in Table 18.2, we fitted an intrinsic (concentration-independent) transport rate for each drug to closely approximate the experimental %HIA. This... 

In addition to the mechanistic simulation of absorptive and secretive saturable carrier-mediated transport, we have developed a model of saturable metabolism for the gut and liver that simulates nonlinear responses in drug bioavailability and pharmacokinetics [19]. Hepatic extraction is modeled using a modified venous equilibrium model that is applicable under transient and nonlinear conditions. For drugs undergoing gut metabolism by the same enzymes responsible for liver metabolism (e.g., CYPs 3A4 and 2D6), gut metabolism kinetic parameters are scaled from liver metabolism parameters by scaling Vmax by the ratios of the amounts of metabolizing enzymes in each of the intestinal enterocyte compart-... 

Neither /3-carotene-ds nor retinol-d4 were detected in plasma until 5 hr after the jS-carotene-ds was ingested (see expanded insets in left panels of Fig. 4). Therefore, a gastrointestinal (GI) delay compartment of 4.5 hr and an enterocyte compartment were added to the model. The delay represents the time necessary for /3-carotene-dg (taken with the breakfast) to pass through the gastrointestinal tract and form lipid micelles in preparation for absorption by the enterocyte. Reducing the FTC from the GI delay compartment to the plasma /3-carotene compartment was not an effective way to represent the delay because it flattened the first slope (rise) of the plasma /3-carotene-dg concentration-time curve, whereas adding the... 

Once the delay and enterocyte compartments were added, the initial slope (rise) in the plasma j3-carotene-dg concentration-time curve was still shallower than the rise observed with the experimental observations. Reasoning that the initial sharp rise in the plasma j8-carotene-dg data represented chylomicron /3-carotene rapidly entering the plasma, we increased the FTC of /3-carotene from the enterocyte compartment to the plasma chylomicron compartment until the initial slope (rise) in the model-predicted plasma -carotene-dg concentration-time curve matched the rise that occurred in the experimental observations as shown in Fig. 5, left panel. 

Adding the delay and enterocyte compartments and increasing the FTC of /3-carotene from the enterocyte compartment to the plasma chylomicron compartment produced an intermediate model that predicted the initial rise in plasma /3-carotene-dg concentration very well. At the same time, this version of the model predicted a single peak with a shoulder (Fig. S, left panel) for the plasma /3-carotene-dg concentration-time curve instead of the two peaks indicated by the experimental observations. This discrepancy was resolved by increasing the FTC for /3-carotene from the plasma chylomicron compartment to the liver /3-carotene compartment (Fig. 5, right panel). The two /3-carotene peaks were not resolved when this FTC was too small (see left panel). 

FIG. S. Model prediction of the initial rise in plasma j3-carotene after adding delay compartment (left panel) and the resolution of the plasma j8-carotene peaks after adding an additional (enterocyte) compartment and adjusting several FTCs (right panel). 

Fig. 6 This schematic is an illustration of the GIT advanced compartmental transit model (stomach, seven small intestine compartments, colon, and nine enterocytes). The administered drug, after dissolution, becomes available for passive absorption and efflux secretion. The rate of drug transfer into and out of enterocyte compartments for each GIT lumen compartment is calculated by using the concentration gradient across the apical and basolatmal membranes. This figure is published with permission (Agoram et al. 2001)...

The total rate of gut metabolism includes all the enzymes (i.e., individual CYPs and CYP abundances, index i) that exist in the gut enterocyte compartments (index j) (Gastroplus 5.0, SimulationsPlus, Inc., Lancaster, CA). The CYP450 enzymes are present in the gut in smaller quantities ( 20 times less) than in the liver however, in some cases their contribution to metabolism is similar to what occurs in the liver. This is true for drugs that are highly bound to plasma proteins and have limited access to liver hepatocyte enzymes (Agoram et al. 2001). GastroPlus Manual version 6.0 describes the metabolic activity of aU gut enzymes in (8). 

The coupling of solute transport in the GI lumen with solute lumenal metabolism (homogeneous reaction) and membrane metabolism (heterogeneous reaction) has been discussed by Sinko et al. [54] and is more generally treated in Cussler s text [55], At the cellular level, solute metabolism can occur at the mucosal membrane, in the enterocyte cytosol, and in the endoplasmic reticulum (or microsomal compartment). For peptide drugs, the extent of hydrolysis by lumenal and membrane-bound peptidases reduces drug availability for intestinal absorption [56], Preferential hydrolysis (metabolic specificity) has been targeted for reconversion... 

Vmaxiinjlux or efflux) = Maximal velocity of the saturable transporter Km(injiux or efflux) = Michaelis constant for the saturable transporter Q = Concentration of drug inside the lumen of the intestine CSnt(i) = Concentration of drug inside the enterocyte in compartment i... 

The arrow with an asterisk indicates the site of entry of the oral Se tracer. Arrows between compartments represent pathways of fractional transport. Compartments depicted as rectangles represent delays. Compartments G1, G2, G3, 3 gut compartments, probably the small intestine ENT, enterocytes (intestinal cells) HPL, compartment in hepato-pancreatic subsystem or lymphatic system L/P, liver and pancreas LI, large intestine T1, T2, peripheral tissues, e.g., skeletal muscle, bone, kidney. Feces and urine compartments are drawn in the shape of test tubes to represent fractional (single) collections. The model includes absorption distributed along the gastrointestinal tract, enterohepatic recirculation, four kinetically distinct plasma pools, P1-P4, a subsystem consisting of liver and pancreas, and a slowly turning-over tissue pool. 

In summary, a lipid molecule on its route from the luminal bulk phase into the intracellular compartment of an enterocyte has to overcome two unstirred water layers and one plasma membrane of lipid bilayer structure. The unstirred water layer on the luminal side partly coincides with the mucus gel and the glycocalyx relatively little is known of the importance of these diffusional barriers. 

Fig. 1. Profile of the concentration gradient (C,-C4) from the luminal bulk phase (L) across the brush border plasma membrane (M) to the intracellular compartment (IC) of the enterocyte. Adjacent to the membrane, on both the luminal and the intracellular side there is an unstirred water layer (UWL). It should be noted that this diagram does not attempt to present the relative dimensions of the two unstirred water layers and the plasma membrane. The concentration gradient will have a different appearance in the case of a lipid towards which the membrane permeability is low (panel A) compared to the case where the resistance of the unstirred water layer against diff.ision of the lipid is high while the lipid readily transverses the plasma membrane (panel B). After Thomson and Dietschy [8).

These examples illustrate interactions of bile salts with cellular lipid-metabolizing enzymes which have been demonstrated in vitro. However, without information regarding the concentrations of bile salts in the cellular compartments where the reactions are occurring, the physiological role of intracellular bile salts in the handling of these various lipids cannot be determined. It is likely that bile salts exist largely within the cell in protein-bound form or associated with membranes. In these situations, local concentrations might be achieved sufficient to affect enzymic activities. At present, the role of bile salts in lipid metabolism in the enterocyte is far from clear. 

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