Whitington P F, Kehrer B H, Whitington S H, Shneider B, Black D D
Department of Pediatrics, University of Chicago Pritzker School of Medicine, Wyler Children's Hospital, Illinois 60637.
Hepatology. 1989 Mar;9(3):393-7. doi: 10.1002/hep.1840090308.
A major factor in poor bioavailability of cyclosporine in children undergoing orthotopic liver transplantation appears to be poor absorption of the drug. Our hypothesis is that the Roux-en-Y choledochojejunostomy used for biliary drainage in these children causes cyclosporine malabsorption by reducing the length of bowel available for absorption and by distally displacing the entry of bile into the intestine. In these experiments, we determined the effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in Sprague-Dawley rats. Experimental rats (n = 24) were prepared for study by constructing self-emptying jejunal blind loops. Sham rats (n = 9) had jejunal transection and reanastomosis. Control rats (n = 26) had no operation. Two to 4 weeks later, chronic biliary-enteric fistulae were formed in all animals. In experiments, [3H]cyclosporine was delivered into the duodenum while the site of bile delivery varied. Hourly and cumulative [3H]cyclosporine excretion into bile was quantitated, which our preliminary data show to be a valid estimate of absorption. In control rats, bile was delivered into the duodenum or was replaced with saline and sucrose solution. In experimental rats, bile was infused either into the duodenum, which tested bowel shortening only, or into the proximal end of the blind loop, which tested the combined effects of bowel shortening and distal displacement of bile entry. In sham rats, bile was infused into the duodenum, which controlled for previous abdominal surgery, or into the midjejunum, which tested for distal bile entry only. Two effects of biliary enteroenterostomy on cyclosporine absorption were observed.(ABSTRACT TRUNCATED AT 250 WORDS)
对于接受原位肝移植的儿童来说，环孢素生物利用度差的一个主要因素似乎是药物吸收不良。我们的假设是，这些儿童用于胆汁引流的 Roux-en-Y 胆总管空肠吻合术通过减少可用于吸收的肠段长度以及使胆汁进入肠道的部位向远端移位，导致环孢素吸收不良。在这些实验中，我们确定了胆肠吻合术对经肠道给予环孢素的 Sprague-Dawley 大鼠药代动力学的影响。通过构建自排空空肠盲袢来准备实验大鼠（n = 24）以供研究。假手术大鼠（n = 9）进行空肠横断和再吻合。对照大鼠（n = 26）未做手术。2 至 4 周后，所有动物均形成慢性胆肠瘘。在实验中，当胆汁输送部位不同时，将[3H]环孢素注入十二指肠。对每小时和累积的[3H]环孢素胆汁排泄量进行定量，我们的初步数据表明这是吸收的有效估计值。在对照大鼠中，胆汁被注入十二指肠或用盐水和蔗糖溶液替代。在实验大鼠中，胆汁要么注入十二指肠（仅测试肠段缩短的影响），要么注入盲袢近端（测试肠段缩短和胆汁进入部位向远端移位的综合影响）。在假手术大鼠中，胆汁注入十二指肠（控制先前腹部手术的影响）或注入空肠中部（仅测试胆汁向远端进入的影响）。观察到了胆肠吻合术对环孢素吸收的两种影响。（摘要截短于 250 字）
