More Relevant Prediction for In Vivo Drug Interaction of Candesartan Cilexetil on Hepatic Bile Acid Transporter BSEP Using Sandwich-cultured Hepatocytes

Abstract Treatment with high dose human GH, although an effective anabolic agent, has been associated with increased incidence of sepsis, inflammation, multiple organ failure, and death in critically ill patients. We hypothesized that GH might increase mortality by exacerbating cholestasis through modulation of bile acid transporter expression. High dose GH was continuously infused over 4 d into rats, and on the final day lipopolysaccharides were injected. Hepatic bile acid transporter expression was measured by Northern analysis and immunoblotting and compared with serum markers of cholestasis and endotoxinemia. Compared with non-GH-treated controls, GH increased endotoxin-induced markers of cholestasis and liver damage as well as augmented IL-6 induction. In endotoxinemia, GH treatment significantly induced multidrug resistance-associated protein 1 mRNA and protein and suppressed organic anion transporting polypeptides, Oatp1 and Oatp4, mRNA, suggesting impaired uptake of bilirubin and bile acids at the basolateral surface of the hepatocyte, which could contribute to the observed worsening of cholestasis by GH. This study of endotoxinemia may thus provide a mechanistic link between GH treatment and exacerbation of cholestasis through modulation of basolateral bile acid transporter expression in the rat hepatocyte.

Download Full-text

Ileal bile acid transporter inhibition, CYP7A1 induction, and antilipemic action of 264W94

The Journal of Lipid Research ◽

10.1194/jlr.m200121-jlr200 ◽

2002 ◽

Vol 43 (8) ◽

pp. 1320-1330 ◽

Cited By ~ 43

Author(s):

Carolyn Root ◽

Chari D. Smith ◽

Scott S. Sundseth ◽

Heather M. Pink ◽

Joan G. Wilson ◽

...

Keyword(s):

Bile Acid ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Membrane Vesicles ◽

Human Model ◽

Diurnal Fluctuation ◽

Bile Acid Transporter ◽

Acid Transporter

264W94 was designed to inhibit the ileal bile acid transporter (IBAT). Evaluated in vitro, 264W94 dose-dependently inhibited sodium-dependent uptake of 10 μM [3H]taurocholic acid (TC) by rat and monkey brush border membrane vesicles with IC50s of 0.24 μM and 0.41 μM, and had a competitive profile with Ki of 0.2 μM against TC in Chinese hamster ovary cells expressing human IBAT. In distal ileum in situ, 1–10 μM of 264W94 rapidly decreased uptake of 3mM TC by 24–39%, with corresponding decreases in biliary recovery. In rats and mice in vivo, oral 264W94 decreased absorption of TC analog, 23,25-75Se-homocholic acid taurine (75SeHCAT; quantitated in feces), with ED30 of 0.02 mg/kg bid. 75SeHCAT traced through the GI-tract revealed that peak (97%) inhibition of 75SeHCAT absorption by the distal quarter of small intestine occurred at 4 h after single dose of 264W94 (0.1 mg/kg). Inhibition of IBAT by 264W94 in rats was associated with compensatory, same-day, 4-fold induction of hepatic cholesterol 7α-hydroxylase (CYP7A1) activity, exhibiting normal diurnal fluctuation for 3 days of dosing. In diet induced hypercholesterolemic rats, 264W94 (0.03–1.0 mg/kg bid) dose-dependently reduced serum LDL+VLDL cholesterol up to 61%.In conclusion, 264W94 is a potent new cholesterol lowering agent that acts through inhibition of IBAT and exhibits activity in a human model.

Download Full-text