Pharmacokinetic interactions of paclitaxel, docetaxel and their vehicles with doxorubicin.
BACKGROUND
The combination of doxorubicin (Dx) with paclitaxel or docetaxel is clinically effective but there are concerns regarding the higher incidence of cardiotoxicity of the combination compared with Dx alone. The mechanism of the increased toxicity is still unclear.


OBJECTIVE
To assess whether there is a pharmacokinetic interaction between paclitaxel, docetaxel or their vehicles and Dx in mice.


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 polysorbate80-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, liver and kidney were much higher in mice concomitantly treated with paclitaxel, docetaxel (dissolved in either cremophor or polysorbate) and cremophor. At 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 were significantly lower in mice treated with the combination than in mice given Dx alone.


CONCLUSIONS
Paclitaxel, docetaxel and cremophor when given together with Dx modify its distribution and metabolism, increasing Dx levels in many tissues including the heart. This might have some bearing on the toxicity of regimens in which Dx is combined with taxanes.
Colombo
T
T
Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Parisi
I
I
Zucchetti
M
M
Sessa
C
C
Goldhirsch
A
A
D'Incalci
M
M
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D000077143:Docetaxel; D004317:Doxorubicin / Q000008:administration & dosage*; D004347:Drug Interactions; D007275:Injections, Intravenous; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008168:Lung / Q000737:chemistry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009206:Myocardium / Q000737:chemistry; D017239:Paclitaxel / Q000008:administration & dosage / Q000031:analogs & derivatives; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage / Q000493:pharmacokinetics; D012016:Reference Values; D013154:Spleen / Q000737:chemistry; D043823:Taxoids; D013997:Time Factors; D014018:Tissue Distribution
D000972:Antineoplastic Agents, Phytogenic; D014677:Pharmaceutical Vehicles; D043823:Taxoids; D000077143:Docetaxel; D004317:Doxorubicin; D017239:Paclitaxel