Pharmacokinetics and biliary excretion of mitoxantrone in rats

The objective of this investigation was to compare the observed biliary clearance (CL(b)) and % of dose excreted in the bile (PD(b)) of mitoxantrone with the predicted values obtained from quantitative structure pharmacokinetic relationship (QSPKR) models. Blood and bile samples were collected from bile duct cannulated rats after an intravenous bolus dose of 0.5 or 2 mg/kg mitoxantrone, and the concentrations were measured by HPLC. Mitoxantrone plasma concentrations exhibited a tri-exponential profile with systemic clearance of 118 +/- 6.8 mL/min/kg. After dosing, 6.08 +/- 2.32% and 5.69 +/- 0.59% of the dose were excreted into bile in unchanged form after a 3-h collection. CL(b) was 7.20 +/- 4.54 and 7.46 +/- 0.62 mL/min/kg after the two doses. With the co-administration of 10 mg/kg GF-120918, a P-glycoprotein and BCRP inhibitor, PD(b) was reduced to 0.69 +/- 0.07%, suggesting that BCRP or P-glycoprotein may play an important role in the biliary elimination of mitoxantrone. Using QSPKR models developed for the biliary excretion of cations/neutral compounds in rats, CL(b) and PD(b) of mitoxantrone were predicted as 5.18 mL/min/kg and 7.21%, respectively, suggesting that the models could be used to predict the biliary excretion of mitoxantrone.