Model-based prediction of plasma concentration and enterohepatic circulation of total bile acids in human
Benjamin Guiastrennec (1), David P. Sonne (2,3), Martin Bergstrand (1), Filip K. Knop (2,3,4) and Mats O. Karlsson (1)
(1) Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden, (2) Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark, (3) Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark, (4) Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Objectives: To predict the enterohepatic circulation of total bile acids (BA) from their plasma concentrations in relation to fat intake.
Methods: Data were obtained from a previously published study [1] involving 30 subjects who were administered 4 test drinks (350 mL) with 0, 2.5, 10 and 40 g fat, respectively, in a cross-over design. Gallbladder volume and total plasma BA concentration were measured repeatedly from 15 min before and up to 240 min after test drink intake. A published mechanism-based gastric emptying model [2], including a gallbladder compartment, was modified in order to predict the enterohepatic circulation of BA. Structural model development and the effect of test drink fat content were based on prior knowledge of BA physiology.
Results: The model featured a gallbladder compartment emptying into the small intestine, implemented as a chain of transit compartments. The bile volume emptied from the gallbladder was a function of the test drink fat content. Upon absorption in the distal end of the small intestine, BA could either be extracted by the liver back to the gallbladder compartment or spill over to the systemic plasma compartment. Hepatic extraction was implemented using a well-stirred model with constant intrinsic clearance (CLint = 285 L/min). Literature values were used for hepatic volume (0.0143 L/kg) and blood flow (3.5 L/h/kg3/4) [3], mean small intestinal transit time (200 min) [4], BA concentration in gallbladder (100 mM) [5] and the fraction of unbound BA in plasma (6.9%) [6]. The model appropriately described the gallbladder volume time-course for all test drinks and the total plasma BA time-course with the exception of the 40-g fat content test drink where concentrations were systematically underpredicted.
Conclusions: The developed enterohepatic circulation model accurately predicted the gallbladder volume and total plasma BA concentrations time-course following the 0, 2.5 or 10-g fat content test drinks. However, the total plasma BA concentrations were systematically underpredicted for the 40-g fat content test drink, indicating a possible threshold effect of fat on BA absorption or hepatic extraction. In the future, the proposed model could be used to predict intestinal BA concentrations from their plasma concentration and their influence on the absorption of lipophilic compounds.
References:
[1] Sonne DP, Rehfeld JF, Holst JJ, Vilsboll T, Knop FK. Postprandial gallbladder emptying in patients with type 2 diabetes: potential implications for bile-induced secretion of glucagon-like peptide 1. Eur. J. Endocrinol. 2014; 171:407–419.
[2] Guiastrennec B, Sonne D, Hansen M, et al. Mechanism-Based Modeling of Gastric Emptying Rate and Gallbladder Emptying in Response to Caloric Intake. CPT Pharmacometrics Syst. Pharmacol. 2016; 5:692–700.
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[4] Jamei M, Turner D, Yang J, et al. Population-based mechanistic prediction of oral drug absorption. AAPS J. 2009; 11:225–237.
[5] Hofmann AF. Enterohepatic circulation of bile acids. Handb. Physiol. - Gastrointest. Syst. 1978; 19:567–596.
[6] Cowen AE, Korman MG, Hofmann AF, Thomas PJ. Plasma disappearance of radioactivity after intravenous injection of labeled bile acids in man. Gastroenterology 1975; 68:1567–1573.
Acknowledgement: This work was supported by the IMI consortium Orbito (http://www.imi.europa.eu/content/orbito).