Acute cardiovascular and renal changes induced by mitoxantrone in rabbits. A pharmacokinetic approach

Abstract

The acute effects of a single i.v. bolus injection of mitoxantrone (MX), a cytostatic drug, on mean arterial pressure (MAP), left ventricular pressure (LVP), dp/dt max and ECG, were investigated at different doses (1,2,3,5 and 10 mg/kg) in conscious rabbits. Low values of MAP, LVP and dp/dt max and increased heart rate were observed at 2 h after injection at all dose levels exceeding 1 mg/kg. Plasma kinetics and urinary elimination of MX were determined by high-pressure liquid chromatography (HPLC) and appraised at two dose levels (1.5 mg/kg and 3 mg/kg). MX plasma decay curve at both doses could be fitted to a curve with three exponential components, with an average elimination (3rd component) half-life of about 3.5 h (1.5 mg/kg) and about 5 h (3 mg/kg), respectively. Renal failure was observed in 3 mg/kg-dosed rabbits (elevation of BUN and plasma creatinine, anuria), and resulted in a considerable delay in the MX plasma decay and in a depressed urinary elimination of MX. All but one rabbit died within 24 h. The 1.5 mg/kg-dosed rabbits survived till 24 h, without signs of renal failure, with a 24 h urinary MX recovery of 20%.