Pharmacology and Toxicology of Cremophor EL Diluent

Dorr, Robert T.

doi:10.1177/10600280940280s503

Cited by 214 publications

(133 citation statements)

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“…First, it allows a drug sustained release, a point of major importance because it has been reported that cancer cell sensitivity to paclitaxel concentration increases significantly with the increasing duration of exposure to the drug in vitro due to an increased probability of arresting the cell cycle during the late G 2 or M phase (56,57). Second, LNCs are obtained without the use of Cremophor-EL, the nonionic surfactant in the Taxol formulation that displays a wide variety of intrinsic toxic side effects that limit the amount of drug that can be safely given (58). Third, LNCs target the intracellular compartment in which they likely represent stable drug reservoirs (27).…”

Section: Discussionmentioning

confidence: 99%

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Garcion

Lamprecht

Heurtault

et al. 2006

Molecular Cancer Therapeutics

172

107

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By focusing on rat glioma, we elucidated whether new lipid nanocapsules (LNC) were able to improve anticancer hydrophobic drug bioavailability while also overcoming multidrug resistance. Blank LNCs and LNCs loaded with the antineoplastic agent paclitaxel were formulated by an emulsion inversion phase process. Expression of efflux pumps by rat glioma cells was assessed by reverse transcription-PCR, Western blot, and immunohistochemistry, and their activity was followed using the tracer 99 Tc m -methoxyisobutylisonitrile. Modalities of LNC action were addressed by using confocal microscopy detection of fluorescently labeled LNCs, fluorescence-activated cell sorting, high-performance liquid chromatography measurement of paclitaxel release, and analysis of tumor cell growth. This revealed an interaction between LNCs and efflux pumps that resulted in an inhibition of multidrug resistance in glioma cells, both in culture and in cell implants in animals. LNCs were able to target the intracellular compartment of glioma cells, a mechanism that was abrogated by using intracellular cholesterol inhibitors but not by clathrin-coated pit or caveolae uptake inhibitors. This result can be correlated to the LNC inhibitory effects on efflux pump activity that is itself known to be stimulated by intracellular cholesterol. In parallel, we showed that paclitaxel-loaded LNCs were active reservoirs from which paclitaxel could be released. Finally, we established that paclitaxel-loaded LNCs were more efficient than the commercially available paclitaxel formulation (Taxol) for clinical use, thus reducing tumor expansion in vitro and in vivo. Considering the physiologically compatible nature of LNC excipients, these data may represent an important step towards the development of new clinical therapeutic strategies against cancers.

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Section: Discussionmentioning

confidence: 99%

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Garcion

Lamprecht

Heurtault

et al. 2006

Molecular Cancer Therapeutics

172

107

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“…Cremophor has been proved to be associated with a number of side effects, including hypersensitivity and neurotoxicity. [5][6][7][8] The use of prophylactic steroids and histamine receptor antagonists as anti-allergic pre-medication may decrease the incidence and severity of acute hypersensitivity reactions. However, milder reactions have still been found to occur in 5%-30% of patients.…”

Section: Introductionmentioning

confidence: 99%

Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery

Wang¹,

Li²,

Wang³

et al. 2011

IJN

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Paclitaxel is a diterpenoid isolated from Taxus brevifolia . It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor ® EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly ( P < 0.01) reduced area under the concentration curve (AUC) 0–∞ (20.343 ± 9.119 μg · h · mL −1 vs 5.196 ± 1.426 μg · h · mL −1 ), greater clearance (2.050 ± 0.616 L · kg −1 · h −1 vs 0.556 ± 0.190 L · kg −1 · h −1 ), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC 0–∞ in liver, lung, and spleen (all P < 0.01), but not in heart or kidney.

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“…It is formulated in Cremophor EL and ethanol (1:1, v/v; Taxol) and is currently administered to patients by intravenous infusion. Oral administration of paclitaxel would offer several advantages, namely (a) medication would no longer require a visit to the out-patient clinic, (b) it may allow the achievement of lasting therapeutic plasma levels and (c) it could prevent the adverse effects caused by the vehicle substance Cremophor EL (Dorr, 1994). Thus far, however, reports on the low oral bioavailability of paclitaxel in mice have discouraged the development of an oral formulation (Eiseman et al, 1994;Fujita et al, 1994).…”

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confidence: 99%

Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833

Asperen

Tellingen²,

Sparreboom³

et al. 1997

Br J Cancer

177

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Pharmacology and Toxicology of Cremophor EL Diluent

Cited by 214 publications

References 0 publications

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

A new generation of anticancer, drug-loaded, colloidal vectors reverses multidrug resistance in glioma and reduces tumor progression in rats

Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery

Enhanced oral bioavailability of paclitaxel in mice treated with the P-glycoprotein blocker SDZ PSC 833

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