title: The co-solvent Cremophor EL limits absorption of orally administered paclitaxel in cancer patients.
abstract: The purpose of this study was to investigate the effect of the co-solvents Cremophor EL and polysorbate 80 on the absorption of orally administered paclitaxel. 6 patients received in a randomized setting, one week apart oral paclitaxel 60 mg m(-2) dissolved in polysorbate 80 or Cremophor EL. For 3 patients the amount of Cremophor EL was 5 ml m(-2), for the other three 15 ml m(-2). Prior to paclitaxel administration patients received 15 mg kg(-1) oral cyclosporin A to enhance the oral absorption of the drug. Paclitaxel formulated in polysorbate 80 resulted in a significant increase in the maximal concentration (C(max)) and area under the concentration-time curve (AUC) of paclitaxel in comparison with the Cremophor EL formulations (P = 0.046 for both parameters). When formulated in Cremophor EL 15 ml m(-2), paclitaxel C(max) and AUC values were 0.10 +/- 0.06 microM and 1.29 +/- 0.99 microM h(-1), respectively, whereas these values were 0.31 +/- 0.06 microM and 2.61 +/- 1.54 microM h(-1), respectively, when formulated in polysorbate 80. Faecal data revealed a decrease in excretion of unchanged paclitaxel for the polysorbate 80 formulation compared to the Cremophor EL formulations. The amount of paclitaxel excreted in faeces was significantly correlated with the amount of Cremophor EL excreted in faeces (P = 0.019). When formulated in Cremophor EL 15 ml m(-2), paclitaxel excretion in faeces was 38.8 +/- 13.0% of the administered dose, whereas this value was 18.3 +/-15.5% for the polysorbate 80 formulation. The results show that the co-solvent Cremophor EL is an important factor limiting the absorption of orally administered paclitaxel from the intestinal lumen. They highlight the need for designing a better drug formulation in order to increase the usefulness of the oral route of paclitaxel
authors.affiliation: Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: M M
authors.initials: MM
authors.lastname: Malingré
authors.forename: J H
authors.initials: JH
authors.lastname: Schellens
authors.forename: O
authors.initials: O
authors.lastname: Van Tellingen
authors.forename: M
authors.initials: M
authors.lastname: Ouwehand
authors.forename: H A
authors.initials: HA
authors.lastname: Bardelmeijer
authors.forename: H
authors.initials: H
authors.lastname: Rosing
authors.forename: F J
authors.initials: FJ
authors.lastname: Koopman
authors.forename: M E
authors.initials: ME
authors.lastname: Schot
authors.forename: W W
authors.initials: WW
authors.lastname: Ten Bokkel Huinink
authors.forename: J H
authors.initials: JH
authors.lastname: Beijnen
mesh_terms: D000284:Administration, Oral; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D004338:Drug Combinations; D005243:Feces / Q000737:chemistry; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014677:Pharmaceutical Vehicles; D011136:Polysorbates / Q000494:pharmacology; D012997:Solvents / Q000494:pharmacology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004338:Drug Combinations; D014677:Pharmaceutical Vehicles; D011136:Polysorbates; D012997:Solvents; C000515:cremophor EL; D016572:Cyclosporine; D017239:Paclitaxel; D005990:Glycerol