Effect of experimental acute renal and hepatic failure on absorption of tacrolimus in rat small intestine.
The objective of this study is to evaluate the effect of acute renal or hepatic failure on the intestinal absorption of tacrolimus. Simultaneous perfusion study in rat small intestine revealed that the extent of absorption into blood vessels was decreased in the jejunum and the ileum of rat of acute renal failure due to the decrease in the uptake of tacrolimus into enterocytes. In contrast, there observed no significant changes in tacrolimus absorption in rat of acute hepatic failure. Since it has been reported that tacrolimus absorption is regulated mainly by Cytochrome P-450 (CYP) mediated metabolism in the jejunum, but by P-glycoprotein (P-gp) mediated efflux in the ileum, these factors might contribute to the changes in intestinal absorption of tacrolimus in rat of acute renal failure. Enzyme inhibitor, ketoconazole, was co-perfused with tacrolimus to specify the effect of CYP and P-gp. However, since ketoconazole failed to recover the permeability in the jejunum and ileum of rat of acute renal failure, it is considered that the changes in CYP or P-gp functions might not be involved in the decreased uptake of tacrolimus. This type of kinetic study in rats should be valuable to identify the precise mechanisms of drug absorption and the effects of various diseases on it, such as acute renal or hepatic failure.
Tamura
Shigeki
S
Fujisawa Pharmaceutical Co., LTD., Osaka, Japan. shigeki_tamuru@po.fujisawa.co.jp
Ohike
Atsuo
A
Tokunaga
Yuji
Y
Ibuki
Rinta
R
Amidon
Gordon L
GL
Sezaki
Hitoshi
H
Yamashita
Shinji
S
D058186:Acute Kidney Injury / Q000378:metabolism*; D000818:Animals; D007408:Intestinal Absorption / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000378:metabolism*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D016559:Tacrolimus / Q000378:metabolism*
D016559:Tacrolimus