Diltiazem increases blood concentrations of cyclized cyclosporine metabolites resulting in different cyclosporine metabolite patterns in stable male and female renal allograft recipients

1 Six male and six female stable renal allograft recipients under cyclosporine immunosuppression and without concomitant therapy with drugs known either to induce or inhibit CYP3A enzymes were included in the study and received 180 mg day(-1) diltiazem for 1 week in a two-period cross-over fashion. Cyclosporine (352 +/- 56 mg day(-1)) was given in two daily oral doses. The daily doses were not changed during the study. Blood samples were collected for 12 h after receiving cyclosporine alone and after receiving diltiazem in addition for 1 week. Cyclosporine and nine of its metabolites were quantified using h.p.l.c. 2 Co-administration of diltiazem caused a 1.6 fold increase of the AUC(0,12 h) of cyclosporine and a 1.7 fold increase of the AUC(0,12 h) of its metabolites. Analysis of the metabolite patterns showed an over-proportional increase of the AUC(0,12 h) of the cyclized metabolites AM1c (2.6 fold) and AM1c9 (2.2 fold). The AUC(0,12 h) values of cyclosporine and the hydroxylated metabolites increased less than two fold. 3 Differences of the AUC(0,12 h) values of cyclosporine with and without diltiazem were significantly higher in female than in male patients (P < 0.02). The differences in the AUC(0,12 h) values of the metabolites, especially AM1c, tended to be higher in female patients as well. 4 It is concluded that coadministration of diltiazem not only increases the blood concentration of cyclosporine but also those of its metabolites, leads to a shift of the metabolite pattern towards cyclized metabolites, and that the pharmacokinetic changes under diltiazem administration are more prominent in female than in male patients.