Chan F K, Shaffer E A
Department of Medicine, Faculty of Medicine, The University of Calgary, Alberta, Canada.
Transplantation. 1997 Jun 15;63(11):1574-8. doi: 10.1097/00007890-199706150-00006.
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.
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.
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.
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.
以往关于环孢素诱导胆汁淤积的研究存在人类研究中遇到的混杂因素以及急性动物实验中的差异等缺陷。甚至环孢素的载体聚氧乙烯蓖麻油（克列莫佛EL）也被认为与胆汁淤积有关。本研究的目的是在稳态条件下，研究环孢素如何影响大鼠模型中的胆盐动力学和胆汁脂质分泌。
三组雄性Lewis大鼠（n = 10）每天皮下注射环孢素（CsA；10 mg/kg体重）、克列莫佛或氯化钠（对照），持续1周。在最后一次注射后18小时进行24小时胆汁收集。第一小时的胆汁输出量测量胆汁流量和有机胆汁溶质分泌率。用洗脱技术测定胆盐池大小和基础合成量。
CsA使基础胆汁流量和胆盐分泌显著降低25%。胆盐合成被抑制45%（CsA：3.50±0.8微摩尔/克肝脏/24小时，对照：6.31±1.17微摩尔/克肝脏/24小时；P<0.05），这导致胆盐池大小减少28%（CsA：16.9±1.9微摩尔/克肝脏，对照：23.6±2.0微摩尔/克肝脏；P<0.05）。非胆盐依赖性胆汁流量显著受到抑制（29%），而胆盐依赖性胆汁流量仅略有减少。胆汁磷脂输出量减少23%（CsA：11.7±0.8纳摩尔/分钟/克肝脏，对照：15.2±1.1纳摩尔/分钟/克肝脏；P<0.05），但胆固醇分泌未改变，导致胆固醇饱和指数增加29%（CsA：0.40±0.03，对照：0.31±0.02；P<0.05）。克列莫佛对胆汁分泌或胆盐动力学无显著影响。
CsA通过降低胆汁流量和胆盐分泌诱导胆汁淤积。其对胆盐合成的抑制减少了胆盐池大小。该药物抑制胆盐和磷脂分泌，而胆固醇分泌无相应变化，从而提高了胆汁中的胆固醇饱和度，这是胆结石形成的潜在风险。
