Stone B G, Udani M, Sanghvi A, Warty V, Plocki K, Bedetti C D, Van Thiel D H
Gastroenterology. 1987 Aug;93(2):344-51.
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.
环孢素A（CyA）在相当一部分移植患者中会导致胆汁淤积。分别给不同组的大鼠腹腔注射5、10和15毫克/千克体重的CyA或Miglyol 812溶媒，持续1、2和3周，以研究这种胆汁淤积的机制。在1周时，观察到血清CyA水平与CyA剂量增加之间存在剂量反应关系。10毫克/千克和15毫克/千克剂量组在2周时达到了最高的CyA血药浓度。随后的研究使用较小剂量（10毫克/千克）给药3周。与溶媒处理的对照组相比，该剂量导致血清胆汁酸水平显著升高（24.6±4.0对4.3±1.2微摩尔/升，p＜0.001），而血清谷氨酸草酰乙酸转氨酶、血清谷氨酸丙酮酸转氨酶、胆红素、碱性磷酸酶和白蛋白水平以及肝脏结构均无明显变化。与溶媒处理的动物相比，CyA处理使基础胆汁流量降低了35%，胆盐分泌降低了25%。给CyA处理组和溶媒处理组的大鼠静脉注射牛磺胆酸盐（4微摩尔/分钟×千克）2小时，然后在接下来的24小时内耗尽胆盐。将在此期间收集的胆汁样本绘制成胆盐分泌与胆汁流量的关系图。CyA处理组大鼠线性回归的平均斜率为对照组的62%，表明胆盐依赖性胆汁流量降低。将线性回归外推至纵坐标显示，CyA处理使非胆盐依赖性胆汁流量降低了22%。因此，在我们的CyA诱导胆汁淤积的实验模型中，观察到的胆汁流量降低是胆盐依赖性和非胆盐依赖性胆汁流量均降低的结果，并且是在没有明显生化或组织学证据表明存在肝毒性的情况下发生的。
