Differential modulation of cisplatin accumulation in leukocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL.
BACKGROUND
Several clinical studies have shown that polychemotherapy with the taxanes paclitaxel or docetaxel preceded or followed by cisplatin is associated with important schedule-dependent differences in toxicities, such as leukocytopenia. In general, the pharmacokinetics of both drugs during the combined treatment are unaltered, suggesting that a pharmacodynamic interaction might have occurred.


METHODS
In order to gain insight into this pharmacologic interaction, we performed in vitro drug accumulation studies using peripheral blood leukocytes and a panel of tumor and non-malignant cell lines with paclitaxel and docetaxel, as well as with their respective formulation vehicles Cremophor EL and Tween 80.


RESULTS
Our results show a significant reduction in the intracellular cisplatin concentration in leukocytes of up to 42% in the presence of Cremophor EL and Tween 80 as compared to the control. This pharmacodynamic interaction of these surfactants with cisplatin seems to be specific for haematopoietic cells, and does not occur in solid tumor cells.


CONCLUSIONS
The present data suggest that the pharmaceutical vehicles Cremophor EL and Tween 80 might contribute to the reduced cisplatin-associated myelotoxicity observed in the clinical combination chemotherapy studies with paclitaxel and docetaxel.
de Vos
A I
AI
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek), The Netherlands.
Nooter
K
K
Verweij
J
J
Loos
W J
WJ
Brouwer
E
E
de Bruijn
P
P
Ruijgrok
E J
EJ
van der Burg
M E
ME
Stoter
G
G
Sparreboom
A
A
D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005990:Glycerol / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011136:Polysorbates / Q000008:administration & dosage; D013501:Surface-Active Agents / Q000008:administration & dosage
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D014677:Pharmaceutical Vehicles; D011136:Polysorbates; D013501:Surface-Active Agents; D011092:Polyethylene Glycols; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol; D002945:Cisplatin