Advertisement

Cremophor EL

the drawbacks and advantages of vehicle selection for drug formulation
  • H Gelderblom
    Correspondence
    Corresponding author. Tel.: +31-10-439-1754; fax: +31-10-439-1003
    Affiliations
    Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, The Netherlands
    Search for articles by this author
  • J Verweij
    Affiliations
    Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, The Netherlands
    Search for articles by this author
  • K Nooter
    Affiliations
    Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, The Netherlands
    Search for articles by this author
  • A Sparreboom
    Affiliations
    Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, 3075 EA Rotterdam, The Netherlands
    Search for articles by this author

      Abstract

      Cremophor EL (CrEL) is a formulation vehicle used for various poorly-water soluble drugs, including the anticancer agent paclitaxel (Taxol). In contrast to earlier reports, CrEL is not an inert vehicle, but exerts a range of biological effects, some of which have important clinical implications. Its use has been associated with severe anaphylactoid hypersensitivity reactions, hyperlipidaemia, abnormal lipoprotein patterns, aggregation of erythrocytes and peripheral neuropathy. The pharmacokinetic behaviour of CrEL is dose-independent, although its clearance is highly influenced by duration of the infusion. This is particularly important since CrEL can affect the disposition of various drugs by changing the unbound drug concentration through micellar encapsulation. In addition, it has been shown that CrEL, as an integral component of paclitaxel chemotherapy, modifies the toxicity profile of certain anticancer agents given concomitantly, by mechanisms other than kinetic interference. A clear understanding of the biological and pharmacological role of CrEL is essential to help oncologists avoid side-effects associated with the use of paclitaxel or other agents using this vehicle. With the present development of various new anticancer agents, it is recommended that alternative formulation approaches should be pursued to allow a better control of the toxicity of the treatment and the pharmacological interactions related to the use of CrEL.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Jonkman-de Vries J.D
        • Flora K.P
        • Bult A
        • Beijnen J.H
        Pharmaceutical development of (investigational) anticancer agents for parenteral use — a review.
        ECC Newsletter. 1994; 3: 11-14
        • Pinedo H.M
        Review.
        Med. Oncol. Tumor Pharmacother. 1986; 3: 63-69
        • Liu G
        • Fransen E
        • Fitch M.I
        • Warner E.l
        Patient preferences for oral versus intravenous palliative chemotherapy.
        J. Clin. Oncol. 1997; 15: 110-115
        • Hoffman H
        Polyoxythylenglycerol triricinoleat 35 DAC 1979.
        Pharm. Zeit. 1984; 129: 1730-1733
        • Goldspiel B.R
        Guidelines for administration.
        in: McGuire W.P Rowinsky E.K Paclitaxel in Cancer Treatment. Marcel Dekker, New York1995: 175-186
        • Wani M.C
        • Taylor H.L
        • Wall M.E
        • Coggon P
        • McPhail A.T
        Plant antitumor agents. VI.
        J. Am. Chem. Soc. 1971; 93: 2325-2327
        • Adams J.D
        • Flora K.P
        • Goldspiel B.R
        • Wilson J.W
        • Arbuck S.G.I
        Taxol.
        J. Natl. Cancer Inst. Monogr. 1993; 15: 141-147
        • Rowinsky E.K
        • Eisenhauer E.A
        • Chaudhry V
        • Chaudrhy V
        • Arbuck S.G
        Clinical toxicities encountered with paclitaxel (Taxol).
        Semin. Oncol. 1993; 20: 1-15
        • Weiss R.B
        • Donehower R.C
        • Wiernik P.H
        • et al.
        Hypersensitivity reactions from Taxol.
        J. Clin. Oncol. 1990; 8: 1263-1268
        • Eisenhauer E.A
        • ten Bokkel Huinink W.W
        • Swenerton K.D
        • et al.
        European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer.
        J. Clin. Oncol. 1994; 12: 2654-2666
        • Szebeni J
        • Muggia F.M
        • Alving C.R
        Complement activation by Cremophor EL as a possible contributer to hypersensitivity to paclitaxel.
        J. Natl. Cancer Inst. 1998; 90: 300-306
        • Watkins J
        • Ward A.M
        • Appleyard T.N
        Adverse reactions to intravenous anaesthetic induction agents.
        Br. Med. J. 1997; 2: 1084-1085
        • Hüttel M.S
        • Schou Olesen A
        • Stoffersen E
        Complement-mediated reactions to diazepam with Cremophor as solvent (stesolid MR).
        Br. J. Anaesth. 1980; 52: 77-79
        • van Zuylen L
        • Gianni L
        • Verweij J
        • et al.
        Interrelationships of paclitaxel disposition, infusion duration and Cremophor EL kinetics in cancer patients.
        Anticancer Drugs. 2000; 11: 331-337
        • Lorenz W.M
        • Reimann H.J
        • Schmal A
        • et al.
        Histamine release in dogs by Cremophor EL and its derivatives.
        Agent Actions. 1977; 7: 63-67
        • Rowinsky E.K
        • McGuire W.P
        • Guarnieri T
        • Fisherman J.S
        • Christian M.C
        • Donehower R.C
        Cardiac disturbances during the administration of Taxol.
        J. Clin. Oncol. 1991; 9: 1704-1712
        • Theis J.G.W
        • Liau-Chu M
        • Chan H.S.L
        • et al.
        Anaphylactoid reactions in children receiving high-dose intravenous cyclosporine for reversal of tumor resistance.
        J. Clin. Oncol. 1995; 13: 2508-2516
        • Volcheck G.W
        • van Dellen R.G
        Anaphylaxis to intravenous cyclosporine and tolerance to oral cyclosporine.
        Am. Allergy Asthma Immunol. 1998; 80: 159-163
        • Bagnarello A
        • Lewis L.A
        • McHenry M.C
        • et al.
        Unusual lipoproteins induced by the vehicle of miconazole.
        N. Eng. J. Med. 1977; 296: 497-499
        • Kongshaug M
        • Cheng L.S
        • Moan J
        • Rimington C
        Interaction of Cremophor EL with human serum.
        Int. J. Biochem. 1991; 23: 473-478
        • Woodburn K
        • Kessel D
        The alteration of plasma lipoproteins by Cremophor EL.
        Photochem. Photobiol. B. 1994; 22: 197-201
        • Sykes E
        • Woodburn K
        • Decker D
        • Kessel D
        Effects of Cremophor EL on distribution of taxol to serum lipoproteins.
        Br. J. Cancer. 1994; 70: 401-404
        • Kessel D
        • Woodburn K
        • Decker D
        • Sykes E
        Fractionation of Cremophor EL delineates components responsible for plasma alterations and multidrug resistance reversal.
        Oncol. Res. 1995; 7: 207-212
        • Shimomura T
        • Fujiwara H
        • Ikawa S
        • Kigawa J
        • Terakawa N
        Effects of Taxol on blood cells.
        Lancet. 1998; 352: 541-542
        • Windebank A.J
        • Blexrud M.D
        • Groen P.C
        Potential neurotoxicity of the solvent vehicle for cyclosporine.
        J. Pharmacol. Exp. Ther. 1994; 268: 1051-1056
        • Lesser G.J
        • Grossman S.A
        • Eller S
        • Rowinsky E.K
        The distribution of systemically administered [3H]paclitaxel in rats.
        Cancer Chemother. Pharmacol. 1995; 37: 173-178
        • de Groen P.C
        • Aksamit A.J
        • Rakela J
        • Forbes G.S
        • Krom R.A.F
        Central nervous system toxicity after liver transplantation.
        N. Eng. J. Med. 1987; 317: 861-886
        • Sparreboom A
        • van Asperen J
        • Mayer U
        • et al.
        Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine.
        Proc. Natl. Acad. Sci. USA. 1997; 94: 2031-2035
        • Verweij J
        • Clavel M
        • Chevalier B
        Paclitaxel (Taxol) and docetaxel (Taxotere).
        Ann. Oncol. 1994; 5: 495-505
        • Podratz J.L
        • Windebank A.J
        Dialyzer associated neurotoxicity due to a change in fatty acid structure.
        Trans. Am. Soc. Neurochem. 1993; 24: 229
        • Brat D.J
        • Windebank A.J
        • Brimijoin S
        Emulsifier for intravenous cyclosporin inhibits neurite outgrowth, causes deficits in rapid axonal transport and leads to structural abnormalities in differentiating N1E.115 neuroblastoma.
        J. Pharmacol. Exp. Ther. 1992; 261: 803-810
        • Woodcock D.M
        • Jefferson S
        • Linsenmeyer M.E
        • et al.
        Reversal of multidrug resistance phenotype with Cremophor EL, a common vehicle for water-insoluble vitamins and drugs.
        Cancer Res. 1990; 50: 4199-4203
        • Friche E
        • Jensen P.B
        • Sehested M
        • Demant E.F
        • Nissen N.N
        The solvents Cremophor EL and Tween 80 modulate daunorubicin resistance in the multidrug resistant Ehrlich ascites tumor.
        Cancer Commun. 1990; 2: 297-303
        • Schuurhuis G.J
        • Broxterman H.J
        • Pinedo H.M
        • et al.
        The polyethylene castor oil Cremophor EL modifies multidrug resistance.
        Br. J. Cancer. 1990; 62: 591-594
        • Chervinsky D.S
        • Brecher M.L
        • Hoecle M.J
        Cremophor EL enhances Taxol efficacy in a multi-drug resistant C13000 neuroblastoma cell line.
        Anticancer Res. 1993; 13: 93-96
        • Riehm H
        • Biedler J.L
        Potentiation of drug effect by Tween 80 in hamster cells resistant to actinomycin D and daunomycin.
        Cancer Res. 1972; 32: 1195-1200
        • Coon J.S
        • Knudson W
        • Clodfelter K
        • Lu B
        • Weinstein R.S
        Solutol HS 15, nontoxic polyethylene esters of 12-hydroxystearic acid, reverses multidrug resistance.
        Cancer Res. 1991; 50: 4199-4203
        • Zordan-Nudo T
        • Ling V
        • Liu Z
        • Georges S
        Effects of nonionic detergents on P-glycoprotein drug binding and reversal of multidrug resistance.
        Cancer Res. 1993; 53: 897-902
        • Woodcock D.M
        • Linsenmeijer M.E
        • Chojnowski G
        • et al.
        Reversal of multidrug resistance by surfactants.
        Br. J. Cancer. 1992; 66: 62-68
        • Slater L
        • Sweet P
        • Wetzel M
        • Stupecky M
        • Osann K
        Comparison of cyclosporin A, verapamil, PSC-833 and Cremophor EL as enhancing agents of VP-16 in murine lymphoid leukemias.
        Leuk. Res. 1995; 19: 543-548
        • Watanabe T
        • Nakayama Y
        • Naito M
        • Oh-hara T
        • Itoh Y
        • Tsuro T
        Cremophor EL reversed multidrug resistance in vitro but not in tumor-bearing mouse models.
        Anticancer Drugs. 1996; 7: 825-832
        • Sparreboom A
        • Verweij J
        • van der Burg M.E.L
        • et al.
        Disposition of Cremophor EL limits the potential of the multidrug resistance phenotype in vivo.
        Clin. Cancer Res. 1998; 4: 1937-1942
        • Nooter K
        • Sonneveld P
        Clinical relevance of P-glycoprotein expression in hematological malignancies.
        Leuk. Res. 1994; 18: 233-243
        • Fjällskog M.-L
        • Fri L
        • Bergh J
        Is Cremophor EL, the solvent for paclitaxel, cytotoxic?.
        Lancet. 1993; 342: 873
        • Nygren P
        • Csóka K
        • Jonsson B
        • et al.
        The cytotoxic activity of Taxol in primary cultures of tumour cells from patients is partly mediated by Cremophor EL.
        Br. J. Cancer. 1995; 71: 478-481
        • Csóka K
        • Dhar S
        • Fridborg H
        • Larsson R
        • Nygren P
        Differential activity of Cremophor EL and Paclitaxel in patients' tumour cells and human carcinoma cell lines in vitro.
        Cancer. 1997; 79: 1225-1233
        • Bégin M.L
        • Ells G
        • Horrobin D.F
        Polyunsaturated fatty acid-induced cytotoxicity against tumour cells and its relationship to lipid peroxidation.
        J. Natl. Cancer Inst. 1988; 80: 188-194
        • Siegel I
        • Liu T.L
        • Yaghoubzadeh E
        • Keskey T.S
        • Gleicher N
        Cytotoxic effects of free fatty acids on ascites tumour cells.
        J. Natl. Cancer Inst. 1987; 78: 271-277
        • Burton A.F
        Oncolytic effects of fatty acids in mice and rats.
        Am. J. Clin. Nutr. 1991; 53: 1082-1086
        • Liebmann J
        • Cook J.A
        • Lipschultz C
        • Teague D
        • Fisher J
        • Mitchell J.B
        The influence of Cremophor EL on the cell cycle effects of paclitaxel (Taxol) in human tumor cell lines.
        Cancer Chemother. Pharmacol. 1994; 33: 331-339
        • Webster L
        • Linsenmeyer M
        • Millward M
        • Morton C
        • Bishop J
        • Woodcock D
        Measurement of CrEL following Taxol.
        J. Natl. Cancer Inst. 1993; 85: 1685-1690
        • Sparreboom A
        • van Tellingen O
        • Huizing M.T
        • Nooijen W.J
        • Beijnen J.H
        Determination of polyethylene-glyceroltriricinoleate 35 (Cremophor EL) in plasma by pre-column derivatization and reverse-phase high-performance liquid chromatography.
        J. Chromatogr. B. 1996; 681: 355-362
        • Sparreboom A
        • Loos W.J
        • Verweij J
        • et al.
        Quantification of Cremophor EL in human plasma samples using a calorimetric dye-binding microassay.
        Anal. Biochem. 1998; 255: 171-175
        • Brouwer E
        • Verweij J
        • Hauns B
        • et al.
        Linearized colorimetric assay for Cremophor EL.
        Anal. Biochem. 1998; 261: 198-202
        • Kunkel M
        • Meyer T
        • Bohler J
        • Keller E
        • Frahm A.W
        Titrimetric determination of Cremophor EL in aqueous solutions and biofluids.
        J. Pharm. Biomed. Anal. 1999; 21: 911-922
        • Brouwer E
        • Verweij J
        • de Bruijn P
        • et al.
        Measurement of unbound paclitaxel in human plasma.
        Drug Metab. Dispos. 2000; 28: 1141-1145
        • Rischin D
        • Webster L.K
        • Millward M.J
        • et al.
        Cremophor pharmacokinetics in patients receiving 3-, 6-, and 24-hour infusions of paclitaxel.
        J. Natl. Cancer Inst. 1996; 88: 1297-1301
        • Sparreboom A
        • van Tellingen O
        • Nooijen W.J
        • Beijnen J.H
        Nonlinear murine pharmacokinetics of paclitaxel results from the pharmaceutical vehicle Cremophor EL.
        Cancer Res. 1996; 56: 2112-2115
        • van Tellingen O
        • Beijnen J.H
        • Verweij J
        • Scherrenburg E.J
        • Nooijen W.J
        • Sparreboom A
        Rapid esterase-sensitive breakdown of polysorbate 80 and its impact on the plasma pharmacokinetics of docetaxel and metabolites in mice.
        Clin. Cancer Res. 1999; 5: 2918-2924
        • Meerum-Terwogt J
        • Van Tellingen O
        • Nannan Panday V.R
        • et al.
        Cremophor EL pharmacokinetics in a phase I study of paclitaxel (Taxol) and carboplatin in non-small cell lung cancer patients.
        Anticancer Drugs. 2000; 11: 687-694
        • Gelderblom H
        • Verweij J
        • Brouwer E
        • et al.
        Disposition of [G-3H]paclitaxel in a patient with severely impaired renal function.
        Drug Metab. Dispos. 1999; 27: 1300-1305
        • Gianni L
        • Vigano L
        • Locatelli A
        • et al.
        Human pharmacokinetic characterization and in vitro study of the interaction between doxorubicin and paclitaxel in patients with breast cancer.
        J. Clin. Oncol. 1997; 15: 1906-1915
        • Ellis A.G
        • Webster L.K
        Inhibition of paclitaxel elimination in the isolated perfused rat liver by Cremophor EL.
        Cancer Chemother. Pharmacol. 1999; 43: 13-18
        • Sparreboom A
        • van Zuylen L
        • Brouwer E
        • Loos W.J
        • et al.
        Cremophor EL-mediated alteration of paclitaxel distribution in human blood.
        Cancer Res. 1999; 59: 1454-1457
        • van Zuylen L
        • Karlsson M.O
        • Verweij J
        • et al.
        Pharmacokinetic modeling of paclitaxel encapsulation in Cremophor EL micelles.
        Cancer Chemother. Pharmacol. 2001; 47: 309-318
        • Barre J
        • Didey F
        • Delion F
        • Tillement J.-P
        Problems in therapeutic drug monitoring.
        Ther. Drug. Monit. 1988; 10: 133-143
      1. van der Burg MEL, de Wit R, Stoter G, Verweij J. Phase I study of weekly cisplatin and weekly or 4-weekly taxol: a highly active regimen in advanced epithelial cancer. Proc Am Soc Clin Oncol 1998, 17, 1370 (abstr).

        • Rowinsky E.K
        • Gilbert M.R
        • McGuire W.P
        • Noe D.A
        • Grochow L.B
        • Forastiere A.A
        Sequences of taxol and cisplatin.
        J. Clin. Oncol. 1991; 9: 1692-1703
        • Huizing M.T
        • Giaccone G
        • Warmerdam L.J
        • Rosing H
        • Bakker P.J
        Pharmacokinetics of paclitaxel in a dose-escalating and dose-sequencing study in patients with non-small-cell lung cancer.
        J. Clin. Oncol. 1993; 15: 317-329
        • de Vos A.I
        • Nooter K
        • Verweij J
        • et al.
        Differential modulation of cisplatin accumulation in leucocytes and tumor cell lines by the paclitaxel vehicle Cremophor EL.
        Ann. Oncol. 1997; 8: 1145-1150
        • Ma J
        • Verweij J
        • Planting A.S.T
        • et al.
        Docetaxel and paclitaxel inhibit DNA adduct formation and intracellular accumulation of cisplatin in human leukocytes.
        Cancer Chemother. Pharmacol. 1996; 36: 382
        • Badary O.A
        • Abdel-Naim A.B
        • Khalifa A.E
        • Hamada F.M.A
        Differential alteration of cisplatin myelotoxicity by the paclitaxel vehicle Cremophor EL.
        Naunyn-Schmiedeberg Arch. Pharmacol. 2000; 261: 339-344
        • Bertoncello I
        • Kriegler A.B
        • Woodcock D.M
        • Williams B
        • Barber B
        • Nilsson S.K
        Haematopoietic radioprotection by Cremophor EL.
        Int. J. Radiat. Biol. 1995; 67: 57-64
        • Millward M.J
        • Webster L.K
        • Rischin D
        • et al.
        Phase I trial of Cremophor EL with bolus doxorubicin.
        Clin. Cancer Res. 1998; 4: 2321-2329
        • Holmes F.A
        • Madden T
        • Newman R.A
        • et al.
        Sequence-dependent alteration of doxorubicin pharmacokinetics by paclitaxel in a phase I study of paclitaxel and doxorubicin in patients with metastatic breast cancer.
        J. Clin. Oncol. 1996; 14: 2713-2721
        • van Zuylen L
        • Verweij J
        • Sparreboom A
        Role of formulation vehicles in taxane pharmacology.
        Invest. N. Drugs. 2001; 19: 125-141