Effects of tegaserod on bile composition and hepatic secretion in Richardson ground squirrels on an enriched cholesterol diet

Abstract

Background: Tegaserod is effective in treating IBS patients with constipation, and does not alter gallbladder motility in healthy individuals or in patients with IBS. However, it is not known if tegaserod affects the biliary tract in gallstone disease, so to this end the effects of tegaserod on bile composition and hepatic secretion of Richardson ground squirrels maintained on an enriched cholesterol diet were examined.

Results: Animals were fed either a control (0.03%) or enriched (1%) cholesterol diet for 28 days, and treated s.c. with tegaserod (0.1 mg/kg BID) or vehicle. Bile flow, bile acid, phospholipids and cholesterol secretion were measured with standard methods. Tegaserod treatment or enriched cholesterol diet, alone or combination, did not alter body or liver weights. The enriched cholesterol diet increased cholesterol saturation index (CSI), cholesterol concentrations in gallbladder and hepatic duct bile by approximately 50% and decreased bile acids in gallbladder bile by 17%. Tegaserod treatment reversed these cholesterol-induced changes. None of the treatments, drug or diet, altered fasting gallbladder volume, bile flow and bile salts or phospholipid secretion in normal diet and cholesterol-fed animals. However, tegaserod treatment prevented the decreases in bile acid pool size and cycling frequency caused by the enriched cholesterol diet, consequent to re-establishing normal bile acid to concentrations in the gall bladder. Tegaserod had no effect on these parameters with normal diet animals.

Conclusion: Tegaserod treatment results in increased enterohepatic cycling and lowers cholesterol saturation in the bile of cholesterol-fed animals. These effects would decrease conditions favorable to cholesterol gallstone formation.

Figure 1

Biliary lipid concentrations and cholesterol saturation index for gallbladder bile. Bile acids, phospholipids, cholesterol concentrations (nmol/l) and cholesterol saturation index (CSI %) were measured in four groups of animals: VN = vehicle + normal diet (n = 17), VC = vehicle + cholesterol diet (n = 15), TN = tegaserod + normal diet (n = 15), and TC = tegaserod + cholesterol diet (n = 17). Significance (P < 0.05): * less than VC; # less than VN; ## greater than VN.

Figure 2

Biliary lipid concentrations and cholesterol saturation index for hepatic duct bile. Bile acids, phospholipids, cholesterol concentrations (nmol/l) and cholesterol saturation index (CSI %) were measured in four groups of animals: VN = vehicle + normal diet (n = 15), VC = vehicle + cholesterol diet (n = 15), TN = tegaserod + normal diet (n = 16), and TC = tegaserod + cholesterol diet (n = 17). Significance (P < 0.05): * less than VC; ** greater than TN; # less than VN; ## greater than VN.

Figure 3

Hepatic flow rates, pool size and cycling frequency. Hepatic bile flow rate (μl/hr/kg), flow rates (μmol/hr/kg) for bile acids, phospholipids, cholesterol, pool size (μmol/kg) and cycling frequency (cycles/24 h) were measured in four groups of animals: VN = vehicle + normal diet (n = 14), VC = vehicle + cholesterol diet (n = 11), TN = tegaserod + normal diet (n = 16), and TC = tegaserod + cholesterol diet (n = 16). Significance (P < 0.05): * less than VC; ** greater than VC; # less than VN; ## greater than VN.