Compartmental pharmacokinetics and tissue distribution of multilamellar liposomal nystatin in rabbits

The plasma pharmacokinetics of multilamellar liposomal nystatin were studie d in normal, catheterized rabbits after single and multiple daily intraveno us administration of dosages of 2, 4, and 6 mg/kg of body weight, and drug levels in tissues were assessed after multiple dosing. Concentrations of li posomal nystatin were measured as those of nystatin by a validated high-per formance liquid chromatography method, and plasma concentration data were f itted into a two-compartment open model. Across the investigated dosage ran ge, liposomal nystatin demonstrated nonlinear kinetics with more than propo rtional increases in the AUC(0-24) and decreasing clearance, consistent wit h dose-dependent tissue distribution and/or a dose-dependent elimination pr ocess. After single-dose administration, the mean C-max increased from 13.0 7 mu g/ml at 2 mg/kg to 41.91 mu g/ml at 6 mg/kg (P < 0.001); the AUC(0-24) changed from 11.65 to 67.34 mu g.h/ml (P < 0.001), the V-d changed from 0. 205 to 0.184 liters/kg (not significant), the CLt from 0.173 to 0.101 liter s/kg.h (P < 0.05), and terminal half-life from 0.96 to 1.51 h (P < 0.05). T here were no significant changes in pharmacokinetic parameters after multip le dosing over 14 days. Assessment of tissue concentrations of nystatin nea r peak plasma levels after multiple dosing over 15 days revealed preferenti al distribution to the lungs, liver, and spleen at that time point. Substan tial levels were also found in the urine, raising the possibility that rena l excretion may play a significant role in drug elimination. Liposomal nyst atin administered to rabbits was well tolerated and displayed nonlinear pha rmacokinetics, potentially therapeutic peak plasma concentrations, and subs tantial penetration into tissues. Pharmacokinetic parameters were very simi lar to those observed in patients, thus validating results derived from inf ection models in the rabbit and allowing inferences to be made about the tr eatment of invasive fungal infections in humans.