Abstract
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 AUC0–15 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.
Footnotes
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This work was supported by Japan Society for the Promotion of Science [Grant-in-Aid for Scientific Research (C) 20590143].
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.145581.
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ABBREVIATIONS: CsA, cyclosporine A; P-gp, P-glycoprotein; I/R, ischemia-reperfusion; KCZ, ketoconazole; ALT, alanine aminotransferase; HPLC, high-performance liquid chromatography; PAGE, polyacrylamide gel electrophoresis; AUC, area under the concentration-time curve; CLtot, total body clearance; CL/F, oral clearance; Tmax, time of peak blood concentration.
- Received September 1, 2008.
- Accepted October 6, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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