Cholestatic effects of cyclosporine in the rat

Abstract

Background: Previous studies of cyclosporine-induced cholestasis were flawed by confounders encountered in human studies and discrepancies in acute animal experiments. Even the cyclosporine vehicle, polyoxyethylated castor oil (Cremophor EL), had been implicated in cholestasis. The purpose of this study was to investigate how cyclosporine affects bile salt kinetics and biliary lipid secretion in a rat model under steady state conditions.

Methods: Three groups of male Lewis rats (n=10) were given daily subcutaneous injections of either cyclosporine (CsA; 10 mg/kg body weight), Cremophor, or NaCl (control) for 1 week. Twenty-four-hour bile collection was performed 18 hr after the last injection. The first hour's output measured bile flow and organic bile solute secretion rates. Bile salt pool size and basal synthesis were determined with the washout technique.

Results: CsA significantly reduced basal bile flow and bile salt secretion by 25%. Bile salt synthesis was suppressed 45% (CsA: 3.50+/-0.8 micromol/g liver/24 hr vs. control: 6.31+/-1.17 micromol/g liver/24 hr; P<0.05), which resulted in a 28% reduction in the bile salt pool size (CsA: 16.9+/-1.9 micromol/g liver vs. control: 23.6+/-2.0 micromol/g liver; P<0.05). Bile salt-independent flow was significantly suppressed (29%), whereas bile salt-dependent flow was only modestly reduced. Biliary phospholipid output decreased 23% (CsA: 11.7+/-0.8 nmol/min/g liver vs. control 15.2+/-1.1 nmol/min/g liver; P<0.05), but cholesterol secretion was unaltered, resulting in a 29% increase in the cholesterol saturation index (CsA: 0.40+/-0.03 vs. control 0.31+/-0.02; P<0.05). Cremophor had no significant effects on bile secretion or bile salt kinetics.

Conclusions: CsA induces cholestasis by decreasing both bile flow and bile salt secretion. Its suppression of bile salt synthesis reduces the bile salt pool size. The drug inhibits bile salt and phospholipid secretion without a corresponding change in cholesterol secretion and thus elevates cholesterol saturation in bile, a potential risk for gallstone formation.