Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake

Abstract

Bile acids released postprandially modify the rate and extent of absorption of lipophilic compounds. The present study aimed to predict gastric emptying (GE) rate and gallbladder emptying (GBE) patterns in response to caloric intake. A mechanism-based model for GE, cholecystokinin plasma concentrations, and GBE was developed on data from 33 patients with type 2 diabetes and 33 matched nondiabetic individuals who were administered various test drinks. A feedback action of the caloric content entering the proximal small intestine was identified for the rate of GE. The cholecystokinin concentrations were not predictive of GBE, and an alternative model linking the nutrients amount in the upper intestine to GBE was preferred. Relative to fats, the potency on GBE was 68% for proteins and 2.3% for carbohydrates. The model predictions were robust across a broad range of nutritional content and may potentially be used to predict postprandial changes in drug absorption.

Figure 1

Schematic representation of the selected gastric emptying (GE, blue), cholecystokinin (CCK, orange), and gallbladder emptying (GB, green) models structure. The test drink was administered to the stomach (dark gray). The GE was governed by the rate constant K_G, which was inhibited by calories in the upper small intestine (SI) (dark blue). K_UL was the rate constant of calories disappearance from the upper SI, K_DJ from the duodenum, and K_JI from the upper jejunum. Nutrients and calories also disappeared in a nonlinear manner, RA_MAX describing the maximal rate of their absorption and K_M the potency of their absorption. The acetaminophen model (light blue) was characterized by the absorption rate constant (K_A), the clearance (CL), central (V_C), and peripheral volumes (V_P) of distribution and intercompartmental clearance (Q). The gallbladder volume compartment (dark green) was characterized by a production rate (R_prodB) and a release rate constant (K_RB). Nutrients in the duodenum would generate a signal that increased K_RB and releasing bile into the upper SI (light gray, compartment added for illustration purpose). Likewise, nutrients in the duodenum and upper jejunum would generate a signal that respectively released the CCK_F and CCK_L from the pools. Production of CCK_F and CCK_L were mediated by the rates R_prodF and R_prodL. The release from the pools to the plasma was controlled by the release rate constant K_RF and K_RL, on which the nutrient signal would act. Finally, the disappearance of CCK from the plasma was controlled by the disappearance rate constants K_outF and K_outL.

Figure 2

Visual predictive checks of the acetaminophen plasma concentration (top) and gallbladder volume (bottom) time course and stratified by test drink. For each panel, the median (bold lines), 5th and 95th percentiles (thin lines) of the observed data are compared to the 95% confidence intervals (shaded areas) for the median (light gray), 5th and 95th percentiles of the simulated data (blue/dark gray: acetaminophen, green: gallbladder volume) (based on 1,000 simulations). The external validation of acetaminophen was performed by simulation only. The vertical lines (dashed gray) represent the time of the test drink administration. OGTT, oral glucose tolerance test.

Figure 3

Left: model‐based simulations of the time to empty 50% of the stomach content (T_GE50) vs. caloric content stratified by gender and test drink composition. Right: model‐based simulations of the gallbladder ejection fraction vs. the amount of nutrients (differentiation is made between carbohydrates and fats). For each panel different prediction intervals (shaded areas) and the median (solid lines) were calculated based on 1,000 simulations of the development dataset. Dashed lines were added to denote the median T_50GE (left) and median gallbladder ejection fraction (right) of the studied test drinks (labels). OGTT, oral glucose tolerance test.