Fractionation of Cremophor EL delineates components responsible for plasma lipoprotein alterations and multidrug resistance reversal.
Treatment of cancer patients with 3-h infusions of taxol formulated with Cremophor EL resulted in a marked decrease in the electrophoretic mobility of all plasma lipoproteins. Cremophor was fractionated by reverse-phase chromatography to determine which components were responsible for this behavior. Effects of different Cremophor fractions on reversal of multidrug resistance, amino acid transport, and cytotoxicity also were evaluated using murine leukemia cells in culture. Lipoprotein alterations were caused by Cremophor components of intermediate hydrophobicity, which also antagonized amino acid transport and decreased viability of murine leukemia cells. Cremophor components responsible for reversal of multidrug resistance were of greater hydrophobicity. The lipoprotein-altering components of Cremophor could be selectively removed without affecting either taxol solubilization or multidrug-resistant reversal.
Kessel
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D
Department of Pharmacology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Woodburn
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Decker
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D
Sykes
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E
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D005591:Chemical Fractionation; D002851:Chromatography, High Pressure Liquid; D003630:Daunorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004587:Electrophoresis, Agar Gel; D004591:Electrophoresis, Polyacrylamide Gel; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D006801:Humans; D007941:Leukemia P388; D008074:Lipoproteins / Q000097:blood* / Q000737:chemistry; D051379:Mice; D017239:Paclitaxel / Q000378:metabolism / Q000494:pharmacology; D014677:Pharmaceutical Vehicles; D011485:Protein Binding
D000970:Antineoplastic Agents; D008074:Lipoproteins; D014677:Pharmaceutical Vehicles; C000515:cremophor EL; D017239:Paclitaxel; D005990:Glycerol; D003630:Daunorubicin