Model‐Based Prediction of Plasma Concentration and Enterohepatic Circulation of Total Bile Acids in Humans

Abstract

Bile acids released postprandially can modify the rate and extent of lipophilic compounds’ absorption. This study aimed to predict the enterohepatic circulation (EHC) of total bile acids (TBAs) in response to caloric intake from their spillover in plasma. A model for TBA EHC was combined with a previously developed gastric emptying (GE) model. Longitudinal gallbladder volumes and TBA plasma concentration data from 30 subjects studied after ingestion of four different test drinks were supplemented with literature data. Postprandial gallbladder refilling periods were implemented to improve model predictions. The TBA hepatic extraction was reduced with the high‐fat drink. Basal and nutrient‐induced gallbladder emptying rates were altered by type 2 diabetes (T2D). The model was predictive of the central trend and the variability of gallbladder volume and TBA plasma concentration for all test drinks. Integration of this model within physiological pharmacokinetic modeling frameworks could improve the predictions for lipophilic compounds’ absorption considerably.

Population pharmacokinetics of regorafenib in solid tumours: Exposure in clinical practice considering enterohepatic circulation and food intake

“…It should be noted that a limitation of this analysis is that some food intake is assumed, and a more physiologicalbased approach (e.g. as published by Guiastrennec et al 33 ) to describe the EHC of total bile acids, would be required to extend the scope of the model and explore the possible effect of major changes in food intake pattern on exposure.…”

Model‐based data analysis of individual human postprandial plasma bile acid responses indicates a major role for the gallbladder and intestine

“…Several models of bile acid metabolism have been developed previously including the compartmental models developed by Hofmann et al (Hofmann, Molino, Milanese, & Belforte, ; ; Molino, Hofmann, Cravetto, Belforte, & Bona, ; Cravetto, Molino, Hofmann, Belforte, & Bona, ), the more recent exogenous UDCA (Zuo, Dobbins, O'Connor‐Semmes, & Young, ) and endogenous LCA (Woodhead et al, ) focused models, and an individual, data‐driven model of postprandial total bile acid responses (Guiastrennec et al, ). The latter is the most similar to the approach presented here.…”

“…The latter is the most similar to the approach presented here. However, in contrast to the use of total bile acid responses in (Guiastrennec et al, 2018), we included the major individual bile acids and their conjugates. In vivo, differences in bile acid hydrophobicity translate into differences in intestinal and hepatic uptake kinetics such as higher passive uptake of unconjugated bile acids from the intestinal lumen (Krag & Phillips, 1974) and the well-characterized differences in hepatic extraction rates (Gilmore & Thompson, 1981; Marigold, Bull, F I G U R E 5 Subject 4 is distinguished by insensitivity to colon transit speed.…”

Compartmental model to estimate bile acid concentration in different clinical manifestation

“…The atony of gallbladder functioning or intestinal resection leads to abnormal bile secretion and its circulation, which associate to cause lipid imbalance due to lack of its metabolism and aligning disorder of high risk of cholesterol and bile acid in the systemic circulation (4) . Even though the gallbladder is considered to be not so important organ for survival, but its role in bile acid storage and concentrating its composition following the enterohepatic circulation effectively helps in lipid metabolism and absorption (5) . Abnormal functioning of bile or intestinal bile secretion arises due to various pathological disorders such as biliary obstruction, biliary fistula, cholecystectomy, ileal resection, portal-systemic venous shunting, and gallstone.…”