Diltiazem disposition and metabolism in recipients of renal transplants.

Diltiazem is widely prescribed in Australasia as a cyclosporine-sparing agent. On seven separate occasions at 2-week intervals, the authors studied eight patients who had undergone renal transplantation, were treated with cyclosporin A, and were in stable condition. The patients were administered escalating doses of conventional-release diltiazem, and (in an extension study) controlled-diffusion diltiazem, to consider the disposition and metabolism of diltiazem. Blood samples were drawn during a 24-hour period, and the AUC(0)(24) of diltiazem and three major metabolites was determined. Results demonstrated that seven patients had comparable diltiazem metabolite AUC(0)(24) profiles, despite considerable variability in parent diltiazem areas under the curve (AUCs), with DM-DTZ > DA-DTZ > DMDA-DTZ. The eighth patient displayed a different metabolite profile. The controlled-diffusion formulation reduced the interpatient variability in diltiazem AUC(0)(24) from 46-fold to <3-fold, but it did not appear to have release characteristics consistent with the manufacturer's specifications. The apparent bioavailability of the conventional-release diltiazem formulation appeared to be highly variable, and this has implications for its use in recipients of organ transplants. The dosage escalation demonstrated a linear relationship between dose and AUC for diltiazem and for each of the metabolites. There may be a subset of patients who display a different diltiazem metabolite profile.