COMPARTMENTAL PHARMACOKINETICS AND TISSUE DRUG DISTRIBUTION OF THE PRADIMICIN DERIVATIVE BMS-181184 IN RABBITS

The pharmacokinetics of the antifungal pradimicin derivative EMS 18118 4 in plasma of normal, catheterized rabbits were characterized after s ingle and multiple daily intravenous administrations of dosages of 10, 25, 50, or 150 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of BMS 181184 were dete rmined by a validated high-performance liquid chromatography method, a nd plasma data were modeled into a two-compartment open model. Across the investigated dosage range, EMS 181184 demonstrated nonlinear, dose -dependent kinetics with enhanced clearance, reciprocal shortening of elimination half-life, and an apparently expanding volume of distribut ion with increasing dosage, After single-dose administration, the mean peak plasma BMS 181184 concentration (C-max) ranged from 120 mu g/ml at PO mg/kg to 648 mu g/ml at 150 mg/kg; the area under the concentrat ion-time curve from 0 to 24 h (AUC(0-24)) ranged from 726 to 2.130 mu g . h/ml, the volume of distribution ranged from 0.397 to 0.799 liter/ kg, and the terminal half-life ranged from 4.99 to 2.31 h, respectivel y (P < 0.005 to P < 0.001), No drug accumulation in plasma occurred af ter multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, althoug h mean elimination half-lives were slightly longer. Multiple daily dos ing at 150 mg/kg was associated with enhanced total clearance and a si gnificant decrease in AUC(0-24) below the values obtained at 50 mg/kg (r < 0.01) and after single-dose administration of the same dosage (P < 0.05), Assessment of tissue BMS 181184 concentrations after multiple dosing over 16 days revealed substantial uptake in the lungs, liver, and spleen and, most notably, dose-dependent accumulation of the drug within the kidneys. These findings are indicative of dose- and time-de pendent elimination of EMS 181184 from plasma and renal accumulation o f the compound after multiple dosing.