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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

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

Department of Clinical Pharmacy and Biopharmaceutics, Mie University Graduate School of Medicine, Mie, Japan (K.I., H.Ma.); Department of Pharmacy, Mie University Hospital, Tsu, Mie, Japan (T.I., M.O.); College of Pharmacy, Kinjo Gakuin University, Nagoya, Aichi, Japan (H.Mi.); and School of Pharmacy, Aichi Gakuin University, Nagoya, Aichi, Japan (K.U.)

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.

Address correspondence to: Dr. Masahiro Okuda, Department of Pharmacy, Mie University Hospital, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. E-mail: okudam{at}clin.medic.mie-u.ac.jp