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.