Cyclosporin A (CyA) causes
cholestasis in a significant proportion of transplant patients. Doses of 5, 10, and 15 mg CyA/kg body wt or the
Miglyol 812 vehicle were administered intraperitoneally for 1, 2, and 3 wk to separate groups of rats to investigate the mechanism of this
cholestasis. At 1 wk a dose-response relationship between serum CyA levels and increasing CyA doses was noted. A maximum CyA blood level was achieved by 2 wk with the 10- and 15-mg/kg doses. Subsequent studies were performed using the smaller (10 mg/kg) dose administered for 3 wk. This dose resulted in a marked increase in serum
bile acid levels compared with vehicle-treated controls (24.6 +/- 4.0 vs. 4.3 +/- 1.2 mumol/L, p less than 0.001) without inducing significant changes in
serum glutamic oxaloacetic transaminase, serum
glutamic pyruvic transaminase,
bilirubin,
alkaline phosphatase, and
albumin levels or hepatic architectural alterations. With CyA treatment, baseline bile flow decreased by 35% and
bile salt secretion decreased by 25% compared with vehicle-treated animals.
Cyclosporin A and vehicle-treated rats were infused intravenously with
taurocholate (4 mumol/min X kg) for 2 h and then depleted of
bile salts over the next 24 h. Bile samples collected over this period were graphed as
bile salt secretion versus bile flow. The mean slope of the linear regression for the CyA-treated rats was 62% of the control, demonstrating a decrease in
bile salt-dependent flow. Extrapolation of the linear regression to the ordinate demonstrated a 22% decrease in bile-independent flow with CyA treatment. Therefore, in our experimental model of CyA-induced
cholestasis, the decrease in flow observed was the result of a decrease in both
bile salt-dependent and
bile salt-independent flows and occurred in the absence of significant biochemical or histologically evident hepatotoxicity.