Compartmental pharmacokinetics and tissue drug distribution of the pradimicin derivative BMS 181184 in rabbits

The pharmacokinetics of the antifungal pradimicin derivative EMS 181184 in plasma of normal, catheterized rabbits were characterized after single 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 determined by a validated high-performance liquid chromatography method, and 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 distribution 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 concentration-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, respectively (P < 0.005 to P < 0.001), No drug accumulation in plasma occurred after multiple daily dosing at 10, 25, or 50 mg/kg over 15 days, although mean elimination half-lives were slightly longer. Multiple daily dosing at 150 mg/kg was associated with enhanced total clearance and a significant 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-dependent elimination of EMS 181184 from plasma and renal accumulation of the compound after multiple dosing.