Pharmacokinetic interaction between cyclosporin and diltiazem.

Previous reports have indicated that administration of the calcium antagonist diltiazem results in major changes in the pharmacokinetics of cyclosporin A (CyA). A new clinical trial was undertaken in 22 renal transplant patients receiving a constant dose of cyclosporin to further explore this interaction. Coadministration of diltiazem for one week produced an increase in the blood concentration of CyA and its metabolites 17 and 18 in almost all patients, but no increase in CyA metabolites 1 and 21. The mean whole blood CyA trough level determined by HPLC rose from 117 ng.ml-1 to 170 ng.ml-1 after one week on diltiazem, and the mean trough level of metabolite 17 rose similarly from 184 ng.ml-1 before to 336 ng.ml-1. Based on experiments with microsomes from human liver the effect of diltiazem was due to noncompetitive inhibition of CyA-metabolism by diltiazem, and the increased concentration of metabolite 17 might have been due to stronger inhibition of its secondary metabolism steps.