The effect of biliary enteroenterostomy on the pharmacokinetics of enterally administered cyclosporine in rats.
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)
Whitington
P F
PF
Department of Pediatrics, University of Chicago Pritzker School of Medicine, Wyler Children's Hospital, Illinois 60637.
Kehrer
B H
BH
Whitington
S H
SH
Shneider
B
B
Black
D D
DD
D000714:Anastomosis, Surgical; D000818:Animals; D001646:Bile / Q000378:metabolism; D001652:Bile Ducts / Q000601:surgery*; D002851:Chromatography, High Pressure Liquid; D003524:Cyclosporins / Q000493:pharmacokinetics*; D007421:Intestine, Small / Q000601:surgery*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins