Commercial taxane formulations induce stomatocytosis and increase blood viscosity.
1. Taxanes are antineoplastic drugs which have cardiovascular side effects of unknown mechanism. We investigated their influence on blood viscosity and erythrocyte morphology. 2. Whole blood was incubated in vitro with increasing concentrations of Taxol, Taxotere, paclitaxel (0-100 microM) and the vehicles Cremophor-EL and Tween 80 (0-5% vol) for 1 h at 37 degrees C. Plasma and whole blood viscosity (Haematocrit 45%) were measured and erythrocyte morphology was assessed on glutaraldehyde-fixed cells. The same investigations were performed in seven patients before and after a Taxol-infusion. 3. Taxol and Taxotere induced a dose- and time-dependent stomatocytic shape transformation of erythrocytes. Paclitaxel alone had no effect, but the vehicles cremophor-EL and Tween 80, used in Taxol and Taxotere, respectively, induced a comparable degree of stomatocytosis. This suggests a preferential intercalation of these substances into the inner hemileaflet of the membrane lipid bilayer. Associated with this shape change a dose-dependent increase in plasma and whole blood viscosity was observed. Neither shape nor viscosity changes were reversible upon removal of the agents. After the infusion of 130-300 mg Taxol in patients a slight shift towards stomatocytosis and an increase in whole blood viscosity at high shear rate from 5.09+/-0.30 to 5.44+/-0.38 mPa.s (P<0.05) were confirmed. 4. Commercial taxane drug formulations induce stomatocytosis and increase blood viscosity, which is due to their formulation vehicles. These findings may contribute to the understanding of the cardiovascular side effects of these drugs.
Mark
M
M
Department of Internal Medicine, Kantonsspital, CH-7000 Chur, Switzerland.
Walter
R
R
Meredith
D O
DO
Reinhart
W H
WH
D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D001809:Blood Viscosity / Q000187:drug effects*; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology; D012212:Rheology; D013501:Surface-Active Agents / Q000494:pharmacology; D043823:Taxoids; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D001952:Bridged-Ring Compounds; D013501:Surface-Active Agents; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane; D017239:Paclitaxel