CHOLESTATIC EFFECTS OF CYCLOSPORINE IN THE RAT

Background. Previous studies of cyclosporine-induced cholestasis were flawed by confounders encountered in human studies and discrepancies i n acute animal experiments. Even the cyclosporine vehicle, polyoxyethy lated castor oil (Cremophor EL), had been implicated in cholestasis. T he purpose of this study was to investigate how cyclosporine affects b ile salt kinetics and biliary lipid secretion in a rat model under ste ady 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 injectio n. The first hour's output measured bile flow and organic bile solute secretion rates. Bile salt pool size and basal synthesis were determin ed with the washout technique. Results. CsA significantly reduced basa l bile flow and bile salt secretion by 25%. Bile salt synthesis was su ppressed 45% (CsA: 3.50+/-0.8 mu mol/g liver/24 hr vs. control: 6.31+/ -1.17 mu mol/g liver/24 hr; P<0.05), which resulted in a 28% reduction in the bile salt pool size (CsA: 16.9/-1.9 mu mol/g liver vs. control : 23.6-2.0 mu mol/g liver; P<0.05). Bile salt-independent flow was sig nificantly 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<0.0 5), but cholesterol secretion was unaltered, resulting in a 29% increa se in the cholesterol saturation index (CsA: 0.40+/-0.03 vs. control 0 .31+/-0.02; P<0.04). Cremophor had no significant effects on bile secr etion or bile salt kinetics. Conclusions. CsA induces cholestasis by d ecreasing both bile flow and bile salt secretion. Its suppression of b ile 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 bil e, a potential risk for gallstone formation.