Veronika Voronova1, Victor Sokolov1, Dina Chenikova1, Amani Al-Khaifi3,5, Sara Straniero3,5, Chanchal Kumar4,5, Kirill Peskov1, Gabriel Helmlinger2, Mats Rudling3,5, Bo Angelin3,5
1M&S Decisions, Moscow, Russia, 2IMED Biotech Unit, AstraZeneca, Waltham, USA, 3Metabolism Unit, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden, 4IMED Biotech Unit, AstraZeneca R&D, Mölndal SE-431 83, Sweden, 5AstraZeneca-Karolinska Institutet Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Novum, Blickagången 6, SE-141 57 Huddinge, Sweden
Objectives: Bile acids (BA) represent a diverse class of cholesterol metabolism end products undergoing enterohepatic circulation (EHC), with a primary function in maintaining intestinal lipid emulsification. Additionally, BA have pro-tumorigenic, pro-apoptotic and laxative activities; they also activate farnesoid X receptors (FXR) involved in metabolic regulation [1]. Thus, abnormalities in BA biotransformation and distribution within EHC may be associated with pathological conditions including colorectal cancer, hepatic failure, diarrhea. The aim of the current study was to develop a physiologically-based quantitative systems pharmacology (QSP) model allowing for simulations of the three main BA (cholic (CA), chenodeoxicholic (CDCA) and deoxycholic (DCA) acids) dynamics, within EHC, under various conditions.
Methods: The proposed model consists of a system of differential equations describing un(conjugated) CA, CDCA and DCA distributions within the circulation system (systemic; portal serum; sinusoidal space), the hepato-biliary system (liver; bile duct; gallbladder), and the gastro-intestinal (GI) tract (upper and lower intestine; colon). The physiological backbone of the model was based on a model proposed by Hofmann et al. [2]. Briefly, primary BA (CA and CDCA) are formed in the liver, conjugated, stored in the gallbladder, released into the intestine and efficiently reabsorbed, with a minor fraction reaching the colon. Within the GI tract, BA undergo microbial biotransformation: colon is the main site of BA deconjugation and secondary BA (DCA) formation; a minor BA fraction is deconjugated in the lower intestine. Synthesized DCA is reabsorbed in colon or excreted with feces. Food intake promotes gallbladder contraction and stimulates BA release into the small intestine. Postprandial increase of transintestinal BA flux is followed by FXR activation, mirrored by plasma fibroblast growth factor 19 (FGF-19) increase and accompanied by inhibition of cholesterol 7-hydroxylase (CYP7A1) – a major regulatory enzyme in BA synthesis.
Physiological parameters, including organ volumes, plasma flow rates and GI transit time were taken from the literature. Other parameters, corresponding to BA transport and biotransformation, were estimated based on: (1) experimental measurements of BA in different compartments of healthy volunteers (HV); (2) experimental estimates of intestinal and colonic BA permeability. Serum 7α-hydroxy-4-cholesten-3-one (C4) and FGF-19 measurements obtained from HV and patients with EHC abnormalities were used to quantify the effect of FXR activation on BA synthesis.
Results: The model adequately reproduced BA levels in systemic and portal serum, liver, duodenal bile and the GI tract, and predicted average daily BA, FGF-19 and C4 dynamics in serum of HV. Higher fractional hepatic uptake of CA vs CDCA and DCA (89% vs 77 and 75%, respectively) and conjugated vs unconjugated BA (81 vs 57%) drove the differences in BA composition between systemic and portal circulation, which is in agreement with experimental data presented previously [3]. Daily BA profiles in systemic circulation and portal vein were similar. Based on model simulations, we also observed spatial differences in individual BA absorption from the GI tract: ileum is the only site of CA absorption, whereas CDCA and recirculated DCA are absorbed throughout the small intestine. Colon is the main site of de novo synthetized DCA absorption.
Decreased intestinal BA absorption observed in patients with idiopathic BA malabsorption or illeal resection was simulated using the model. Approximately 50% reduction of BA absorption in the lower intestine was followed by colonic BA accumulation, sufficient to stimulate water secretion and induce diarrhea (~ 2mM). Transintestinal BA flux reduction was accompanied by FXR inhibition and an up to 17-fold compensatory BA synthesis stimulation enhancing colonic BA delivery. According to model simulations, FXR stimulation was shown to reduce colonic BA delivery, which supports this therapeutic approach for treatment of BA induced diarrhea.
Conclusions: A QSP model was used to simulate BA dynamics within EHC and identify factors associated with abnormal BA distribution. According to simulations, insufficient FXR activation in patients with BA malabsorption is a key component of colonic BA accumulation.
References:
[1] Schaap et al., “Bile acid receptors as targets for drug development.” Nat Rev Gastroenterol Hepatol. 2014 Jan;11(1):55-67
[2] Hofmann et al., “Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.” J Clin Invest. 1983 Apr;71(4):1003-22
[3] Angelin et al., “Hepatic Uptake of Bile Acids in Man. Fasting and Postprandial Concentrations of Individual Bile Acids in Portal Venous and Systemic Blood Serum.” J Clin Invest. 1982 Oct;70(4):724-31
Reference: PAGE 27 (2018) Abstr 8681 [www.page-meeting.org/?abstract=8681]
Poster: Drug/Disease Modelling - Endocrine