Decreased oral absorption of cyclosporine A after liver ischemia-reperfusion injury in rats: the contribution of CYP3A and P-glycoprotein to the first-pass metabolism in intestinal epithelial cells.
The bioavailability of orally administrated cyclosporine A (CsA) is poor and variable in liver transplantation recipients. Little information is available about the effect of liver ischemia-reperfusion (I/R) injury, which is associated with liver transplantation, on the intestinal first-pass metabolism of CsA. In the present study, we investigated the pharmacokinetics of CsA after liver I/R and assessed the effect of liver I/R via CYP3A and P-glycoprotein (P-gp) on its intestinal first-pass metabolism. When CsA alone was administrated orally, the area under the concentration-time curve (AUC) in the I/R rats was significantly decreased compared with that in the sham rats. On the other hand, there were no significant differences in the AUC between I/R and sham rats when CsA was administrated intravenously or orally with ketoconazole. After intraloop administration of CsA to the small intestine (upper, middle, and lower portions) of the I/R and sham rats, the AUC(0-15 min) in the upper intestine was significantly lower in the I/R rats than in the sham rats. CYP3A activity and the expression levels of P-gp in the upper intestine of the I/R rats were significantly higher than those of the sham rats. Our study clearly demonstrates for the first time that liver I/R decreases the oral bioavailability of CsA and that this is attributable principally to increased first-pass metabolism mediated by CYP3A and P-gp in the upper small intestine. The present findings provide useful information for the etiology of liver I/R injury and appropriate use of CsA after liver transplantation.
Ikemura
Kenji
K
Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Mie, Japan.
Urano
Kimihiko
K
Matsuda
Hiroko
H
Mizutani
Hideki
H
Iwamoto
Takuya
T
Okuda
Masahiro
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001682:Biological Availability; D016572:Cyclosporine / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006900:Hydroxylation; D007166:Immunosuppressive Agents / Q000378:metabolism; D007408:Intestinal Absorption / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D007654:Ketoconazole / Q000493:pharmacokinetics; D008102:Liver Circulation / Q000502:physiology*; D016031:Liver Transplantation / Q000009:adverse effects / Q000502:physiology; D008297:Male; D008861:Microsomes / Q000378:metabolism; D008862:Microsomes, Liver / Q000378:metabolism; D011183:Postoperative Complications / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000378:metabolism*; D013739:Testosterone / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007166:Immunosuppressive Agents; D013739:Testosterone; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D007654:Ketoconazole