Pharmacokinetic interactions of paclitaxel, docetaxel and their vehicles with doxorubicin

Background: The combination of doxorubicin (Dx) with paclitaxel or docetaxe l is clinically effective but there are concerns regarding the higher incid ence of cardiotoxicity of the combination compared with Dx alone. The mecha nism of the increased toxicity is still unclear. Purpose: To assess whether there is a pharmacokinetic interaction between p aclitaxel, docetaxel or their vehicles and Dx in mice. Materials and methods: CDF1 male mice were treated with Dx either alone (10 mg/kg i.v.) or in combination with paclitaxel (25 mg/kg) or docetaxel (25 mg/kg) or their vehicles, i.e., cremophor-ethanol-glucose (cremophor) or po lysorbate80-ethanol-glucose (polysorbate). Four mice were killed 4, 8 or 24 hours after Dx in each experimental group and Dx was assayed in serum and in heart, liver, kidney and spleen by HPLC. Results: Four hours after treatment the concentrations of Dx in heart, live r and kidney were much higher in mice concomitantly treated with paclitaxel , docetaxel (dissolved in either cremophor or polysorbate) and cremophor. A t subsequent times the differences were modest and only reached statistical significance in a few cases. Dx metabolites were modified by concomitant treatment with taxanes or their vehicles. In particular, the levels of Dx aglycone in liver and kidney wer e significantly lower in mice treated with the combination than in mice giv en Dx alone. Conclusions: paclitaxel, docetaxel and cremophor when given together with D x modify its distribution and metabolism, increasing Dx levels in many tiss ues including the heart. This might have some bearing on the toxicity of re gimens in which Dx is combined with taxanes.