Pharmacokinetics of Cyclosporin A after Intravenous Administration to Rats in Various Disease States

抄録

We examine the pharamacokinetic profile of cyclosporin A (CyA) after intravenous administration to rats prepared as models of various disease states found in patients who receive organ transplantations. After intravenous bolus administration to normal rats, the total blood clearance (CL_t) of CyA showed a dose-dependent increase. The CL_t was reduced in anemic (ANE) rats prepared by venesection, in carbon tetrachloride-induced acute hepatic failure (AHF) rats, and in glycerol-induced acute renal failure (ARF) rats. On the other hand, the volume of distribution at a steady state (V_ss) of CyA increased significantly in ANE and aged (AGE) rats. CyA distribution was tissue-specific, and the tissue CyA concentration was disease state-dependent. Linear relationships between the CyA concentration in whole blood and various tissues (liver, kidney and heart) were found in AGE, ANE and AHF animals. However, in ARF rats, tissue concentration was not increased to a great extent in comparison with the other disease models, even though the whole blood CyA concentration was increased. The tissue per blood concentration ratio (K_b), which represented the CyA tissue transfer from systemic circulation, was influenced by the disease state. In the liver, in particular, the K_b increased in the AHF and AGE groups, whereas it decreased in the ANE and ARF rats. The CL_t of CyA was negativerly related to the erythrocyte per plasma concentration ratio (E/P), and the E/P exhibited disease state-dependent changes, suggesting that this ratio is a valuable indicator for predicting variations in CyA total blood clearance in organ transplant patients during episodes of anemia, nephrotoxicity and hepatotoxicity.