Evaluation of Pharmacokinetic Interaction Between Cyclosporin A and Probucol in Rats
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Purpose. The purpose of this study was to clarify the mechanism of pharmacokinetic interaction between cyclosporin A and probucol in clinical cases.
Methods. The whole blood concentration of cyclosporin A was measured after oral administration of cyclosporin A with or without probucol in rats. Cyclosporin A was administered as three types of solutions: the contents of the conventional formulation (Sandimmun® capsule) diluted with corn oil and the contents of the new microemulsion preconcentrate formulation (Neoral® capsule) diluted with saline or corn oil. The solubility of cyclosporin A and another lipophilic agent tacrolimus in water with or without probucol was also measured.
Results. The area under the blood concentration-time curve (AUC) after the administration of Sandimmun® (corn oil) and Neoral® (corn oil) was significantly decreased to 26% and 41% of the control by coadministration of probucol. However in the case of Neoral® (saline), it was unchanged. The terminal elimination rate constant was not affected by probucol in any type of cyclosporin A solution. The solubility of cyclosporin A or tacrolimus in water dropped to 49% or 16% of the respective control in the presence of probucol.
Conclusion. The interaction between cyclosporin A and probucol is caused by the decreased absorption of cyclosporin A partly based on the lowered solubility in the presence of probucol.
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