© 1993 by Oxford University Press
Journal of the National Cancer Institute, Vol. 85, No. 20, 1685-1690,
October 20, 1993
© 1993 Oxford University Press
Measurement of Cremophor EL Following Taxol: Plasma Levels Sufficient to Reverse Drug Exclusion Mediated by the Multidrug-Resistant Phenotype
Peter MacCallum Cancer Institute Melbourne, Victoria, Australia
Correspondence to:Molecular Genetics Laboratory, Peter MacCallum Cancer Institute, 481 Little Lonsdale St., Melbourne, Victoria 3000, Australia.
Background: Paclitaxel (Taxol) is the first of a new class of cytotoxic agents with activity against tumors resistant to other drugs. For clinical use, paclitaxel is currently formulated in a vehicle of 50% ethanol and 50% polyethoxylated surfactant Cremophor EL (Cremophor). We have previously shown that Cremophor will block the P-glycoprotein drug efflux pump responsible for the multidrug-resistant phenotype. Over-expression of P-glycoprotein is one mechanism of in vitro resistance to a number of currently used cytotoxic agents including paclitaxel. Purpose: Our aim was to develop a bioassay to measure plasma levels of Cremophor and to determine whether or not plasma levels of Cremophor achieved during paclitaxel therapy are sufficient to inhibit the activity of the P-glycoprotein. Methods: All patients studied had histologically proven, advanced ovarian carcinoma with measurable or evaluable disease and had received at least one prior platinum-containing regimen. The bioassay used flow cytometry to measure the increase in equilibrium intracellular daunorubicin levels in multidrug-resistant human T-cell leukemia cells (CEM/VLB100) in the presence of a series of concentrations of Cremophor. Levels of Cremophor were measured in plasma from 21 patients after a 3-hour infusion of 135 or 175 mg/m paclitaxel. Both dose levels were given following premedication with oral dexamethasone, intravenous promethazine hydrochloride, and intravenous cimetidine. The Cremophor bioassay involved incubation of CEM/VLB100 cells (5 x 10) for 1 hour with 2 µg/mL daunorubicin in 0.5 mL HL-1 medium plus 0.5 mL plasma prior to flow cytometric analysis. Pretreatment plasma was used to derive a standard curve for the effect of Cremophor on equilibrium daunorubicin levels. All measurements were done in triplicate. Results: In vitro experiments indicated that, for maximal inhibition of P-glycoprotein activity, concentrations of Cremophor of 0.1% (vol/vol) were required. At the end of a 3-hour infusion of paclitaxel, plasma levels of Cremophor in 19 of 21 patients were 0.1% or higher and 0.09% in the remaining two. Concentrations of 5–20 µM paclitaxel dissolved in ethanol without Cremophor did not inhibit P-glycoprotein in this assay. Conclusion: The concentrations of Cremophor measured in plasma drawn from patients after a 3-hour infusion of paclitaxel at 135 or 175 mg/m were found to be sufficient to inhibit P-glycoprotein activity in vitro. Implications: The efficacy of paclitaxel against some tumors may be aided by its administration in a vehicle solution containing Cremophor in quantities that reach concentrations in the plasma sufficient to reverse multidrug resistance of neoplastic cells. [J Natl Cancer Inst 85:1685–1690, 1993]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T.-Y. Kim, D.-W. Kim, J.-Y. Chung, S. G. Shin, S.-C. Kim, D. S. Heo, N. K. Kim, and Y.-J. Bang Phase I and Pharmacokinetic Study of Genexol-PM, a Cremophor-Free, Polymeric Micelle-Formulated Paclitaxel, in Patients with Advanced Malignancies Clin. Cancer Res., June 1, 2004; 10(11): 3708 - 3716. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fogli, R. Danesi, A. Gennari, S. Donati, P. F. Conte, and M. Del Tacca Gemcitabine, epirubicin and paclitaxel: pharmacokinetic and pharmacodynamic interactions in advanced breast cancer Ann. Onc., June 1, 2002; 13(6): 919 - 927. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. K. Ibrahim, N. Desai, S. Legha, P. Soon-Shiong, R. L. Theriault, E. Rivera, B. Esmaeli, S. E. Ring, A. Bedikian, G. N. Hortobagyi, et al. Phase I and Pharmacokinetic Study of ABI-007, a Cremophor-free, Protein-stabilized, Nanoparticle Formulation of Paclitaxel Clin. Cancer Res., May 1, 2002; 8(5): 1038 - 1044. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Venturini, G. Lunardi, L. Del Mastro, M. O. Vannozzi, G. Tolino, G. Numico, M. Viale, I. Pastrone, C. Angiolini, G. Bertelli, et al. Sequence Effect of Epirubicin and Paclitaxel Treatment on Pharmacokinetics and Toxicity J. Clin. Oncol., May 10, 2000; 18(10): 2116 - 2125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. R N. Panday, M. T Huizing, O. van Tellingen, R. A Hakvoort, P. H B Willemse, A. De Graeff, J. B Vermorken, and J. H Beijnen Pharmacologic study of Cremophor EL in cancer patients with impaired hepatic function receiving paclitaxel Journal of Oncology Pharmacy Practice, June 1, 1999; 5(2): 83 - 86. [Abstract] [PDF]
|
|
|
|
 |
|
 G. Y. Kwei, R. F. Alvaro, Q. Chen, H. J. Jenkins, C. E. A. C. Hop, C. A. Keohane, V. T. Ly, J. R. Strauss, R. W. Wang, Z. Wang, et al. Disposition of Ivermectin and Cyclosporin A in CF-1 Mice Deficient in mdr1a P-Glycoprotein Drug Metab. Dispos., May 1, 1999; 27(5): 581 - 587. [Abstract] [Full Text]
|
|
|
|
|
|
E. K. Rowinsky On Pushing the Outer Edge of the Outer Edge of Paclitaxel's Dosing Envelope Clin. Cancer Res., March 1, 1999; 5(3): 481 - 486. [Full Text] [PDF]
|
|
|
|
|
|
L. K Webster, D. M Woodcock, D. Rischin, and M. J Millward Review : Cremophor: Pharmacological activity of an "inert" solubiliser Journal of Oncology Pharmacy Practice, December 1, 1997; 3(4): 186 - 192. [Abstract] [PDF]
|
|