Role of diltiazem on tacrolimus pharmacokinetics in tacrolimus-induced nephrotoxic rats.

Abstract

The effects of diltiazem on tacrolimus pharmacokinetics during tacrolimus-induced nephrotoxicity were studied. In normal rats, co-administration of diltiazem significantly increased AUC(0-infinity) of tacrolimus and reduced total body clearance, Cltot, after intravenous and oral administration. In tacrolimus-induced nephrotoxicity, AUC(0-infinity) of tacrolimus increased 40.7%, while the apparent volume of initial distribution space, Vd1, the apparent volume of steady-state distribution space, Vdss, and Cltot decreased 27.4%, 19.5% and 27.4%, respectively, as compared with the control. Co-administration of diltiazem lowered the AUC(0-infinity) of tacrolimus 36.2% and increased Vd1i.v. 62.8% in Vdss 45.9% and Cltot(i.v) 59.0% in tacrolimus-induced nephrotoxicity, resulting in partial improvement in renal function. These pharmacokinetic alterations due to diltiazem contrasted with those seen in normal rats. As a result, the pharmacokinetic parameters in tacrolimus-induced nephrotoxicity with coadministration of diltiazem resembled those in control rats. Mean tacrolimus concentrations in kidney cortex and medulla in a tacrolimus nephrotoxic group given diltiazem were 33.1% and 44.7% lower than those in a nephrotoxic model due to tacrolimus alone. But the tissue/blood concentration ratio of tacrolimus did not change regardless of the presence of diltiazem. Our findings suggest that co-administration of diltiazem has an advantageous effects on tacrolimus pharmacokinetics to protect against tacrolimus-induced nephrotoxicity.