Description and simulation of a physiological pharmacokinetic model for the metabolism and enterohepatic circulation of bile acids in man. Cholic acid in healthy man.

Abstract

A B S T R A C T A multicompartmental pharmacokinetic model based on physiological principles, experimental data, and the standard mathematical principles of compartmental analysis has been constructed that fully describes the metabolism and enterohepatic cycling in man of cholic acid, a major bile acid. The model features compartments and linear transfer coefficients. The compartments are aggregated into nine spaces based on physiological considerations (liver, gallbladder, bile ducts, jejunum, ileum, colon, portal blood, sinusoidal blood, and general circulation). The transfer coefficients are also categorized according to function: flow, i.e., emptying of gallbladder or intestinal spaces, and circulation of the blood; biotransformation, i.e., conjugation, deconjugation, or dehydroxylation; and transport, i.e., active or passive transport. The model is made time dependent by introducing meals, which trigger discrete increases in gallbladder emptying and intestinal flow. Each space contains three compartments. For cholic acid, these are unconjugated cholic acid, cholylglycine, and cholyltaurine. The model was then used with all existing experimental data to simulate cholic acid metabolism in healthy man over a 24-h period. Satisfactory agreement was obtained between simulated and experimental results for serum bile acid levels, hepatic bile acid secretion, and bile acid secretion into the intestine. The model was also used to classify 16 clinical instances in which the enterohepatic circulation of bile acids is altered

Bile Stress Response in Listeria monocytogenes LO28: Adaptation, Cross-Protection, and Identification of Genetic Loci Involved in Bile Resistance

“…Human bile is composed of individual conjugated and unconjugated bile acids that are present in the small intestine at average concentrations of 5 mM (10,22). L. monocytogenes LO28 is very tolerant of individual conjugated bile acids at concentrations up to 20 mM.…”

Bile acid transporters

“…The enterohepatic circulation maintains a bile acid pool size of approximately 4 mg in mice and 2 to 4 g in humans. This pool cycles multiple times per meal ( 12,13 ) and as such, the intestinal bile acid absorbed may be as much as 20 mg/day in mice and 30 g/day in humans. Hepatic conversion of cholesterol to bile acid balances fecal bile acid excretion and this process represents a major route for elimination of cholesterol from the body ( 14,15 ).…”

Genetic Characterization of the Bile Salt Response in Lactobacillus plantarum and Analysis of Responsive Promoters In Vitro and In Situ in the Gastrointestinal Tract

“…The resulting conjugated bile salts are stored and concentrated in the gall bladder during the fasting state, and after consumption of a fat-containing meal these compounds are released into the duodenum, where they play a major role in the dispersion and absorption of fats, including bacterial phospholipids and cell membranes (34). Bile salts are reintroduced in the liver following their reabsorption in the distal small intestine and colon after deconjugation by the microbiota (16). This deconjugation reaction is performed by bacterial bile salt hydrolases, which are encoded in the genomes of several intestinal bacteria, including Bifidobacterium and Lactobacillus species (7,10,19,33).…”