Effects Of Cremophor EL Research Articles

Advantages and disadvantages of using bovine serum albumin and/or Cremophor EL as extracellular additives during transport studies of lipophilic compounds across Caco-2 monolayers

The effects of Cremophor EL (CEL) and bovine serum albumin (BSA) on the active and passive permeation of BCS class II compounds (felodipine, asimadoline) were studied across Caco-2 cells. The effec ...

Cremophor EL, a non-ionic surfactant, promotes Ca 2+-dependent process of cell death in rat thymocytes

Cremophor EL, a surfactant for pharmaceutical products, augments the cytotoxicity of hydrogen peroxide in rat thymocytes [Iwase, K., Oyama, Y., Tatsuishi, T., Yamaguchi1, J., Nishimura1, Y., Kanada, A., Kobayashi, M., Maemura, Y., Ishida, S., Okano, Y., 2004. Cremophor EL augments the cytotoxicity of hydrogen peroxide in lymphocytes dissociated from rat thymus glands. Toxicol. Lett. 154, 143–148]. The effect of cremophor EL on Ca 2+-dependent process of cell death has been examined using a flow cytometer since hydrogen peroxide increases intracellular Ca 2+ concentration. Cremophor EL at clinically-relevant concentrations greatly increased the population of dead cells in rat thymocytes simultaneously treated with A23187, a calcium ionophore increasing intracellular Ca 2+ concentration. Removal of Ca 2+ from external solution diminished the cremophor EL-induced increase in the dead cell population. Result suggests that Ca 2+-dependent process is involved in the cremophor EL-induced decrease in the cell viability in the simultaneous presence of A23187. The population of cells with hypodiploidal DNA was not increased by the application of cremophor EL and A23187 although the cell viability was greatly decreased, indicating that the type of cell death is necrosis. It is suggested that cremophor EL at clinically-relevant concentrations augments the Ca 2+-dependent process of necrosis.

Cremophor EL augments the cytotoxicity of hydrogen peroxide in lymphocytes dissociated from rat thymus glands

The pharmaceutical uses of cremophor EL, a non-ionic surfactant, are similar to those of polysorbate 80. In our previous study, polysorbate 80 exerted some adverse actions on rat thymocytes under in vitro condition. Therefore, the effects of cremophor EL on thymic lymphocytes were examined using a flow cytometer with appropriate fluorescent dyes. Cremophor EL at 10 μg/ml or more (up to 300 μg/ml) concentration-dependently decreased cellular content of glutathione. The cell viability of thymocytes under control condition was 95.4 ± 1.2% ( n = 7, mean ± S.D.). The incubation of thymocytes with 300 μg/ml cremophor EL or 3 mM hydrogen peroxide for 2 h, respectively, decreased the cell viability to 90.8 ± 2.8% or 91.2 ± 2.6%. However, the simultaneous incubation with cremophor EL and hydrogen peroxide decreased the cell viability to 28.7 ± 8.2%. Cremophor EL at 100 μg/ml accelerated the process of cell death induced by hydrogen peroxide. Results suggest that cremophor EL increases the susceptibility to oxidative stress. Cremophor EL at clinically relevant concentrations may increase the therapeutic potential of some anticancer agents to produce oxidative stress.

Cremophor EL stimulates mitotic recombination in uvsH//uvsH diploid strain of Aspergillus nidulans.

Cremophor EL is a solubilizer and emulsifier agent used in the pharmaceutical and foodstuff industries. The solvent is the principal constituent of paclitaxel's clinical formulation vehicle. Since mitotic recombination plays a crucial role in multistep carcinogenesis, the study of the recombinagenic potential of chemical compounds is of the utmost importance. In our research genotoxicity of cremophor EL has been studied by using an uvsH//uvsH diploid strain of Aspergillus nidulans. Since it spends a great part of its cell cycle in the G2period, this fungus is a special screening system for the study of mitotic recombination induced by chemical substances. Homozygotization Indexes (HI) for paba and bi markers from heterozygous B211//A837 diploid strain were determined for the evaluation of the recombinagenic effect of cremophor EL. It has been shown that cremophor EL induces increase in mitotic crossing-over events at nontoxic concentrations (0.05 and 0.075% v/v).

Effect of Cremophor EL on the pharmacokinetics, antitumor activity and toxicity of doxorubicin in mice.

Cremophor EL (CR) is a solubilizing agent and a modulator of P-glycoprotein (P-gp)-mediated anticancer multidrug resistance. The present study was undertaken to evaluate whether doxorubicin (Dox) pharmacokinetics, therapeutic activity and cardiotoxicity in Swiss albino mice is modified when combined with CR treatment. CR (2.5 ml/kg, i.p) given simultaneously with Dox (20 mg/kg, i.p.) increased Dox levels in plasma, heart, liver and kidneys of healthy mice. Using an Ehrlich ascites carcinoma (EAC)-bearing mice experimental model, CR (2.5 ml/kg) improved the survival and antitumor activity of Dox. The enhanced antitumor activity of Dox was related to a significant increase in EAC tumor cellular Dox content by CR. Furthermore, CR (1 microg/ml) potentiated the in vitro cytotoxicity of Dox in cultured EAC cells. In healthy mice, Dox-induced mortality was markedly reduced by simultaneous treatment with CR. CR enhanced DOX-induced increase in plasma lactate dehydrogenase, creatine phosphokinase (CPK) and CPK-MB isozyme activities, as well as the cardiac malondialdehyde level. CR also increased Dox-induced focal necrotic myocardial lesions. These findings suggest that CR increased DOX antitumor activity and cardiotoxicity as a result of enhancing its bioavailability, and decreased Dox-induced mortality in mice by a mechanism not yet defined.

Effect of density-gradients on the binding of photosensitizing agents to plasma proteins

The binding of photosensitizing agents to low-density lipoprotein is considered an important factor in tumor localization. We examined the affinity of a group of photosensitizers, varying in charge and hydrophobicity, for LDL, under conditions designed to determine whether the high salt concentration involved in conventional KBr gradients affected the results. Density-gradients containing KBr vs D 2O were evaluated; the latter can delineate VLDL and LDL from other plasma components, while the KBr gradient readily resolved VLDL, LDL, HDL and albumin. Distribution of the photosensitizers to plasma fractions was assessed, along with the effect of Cremophor EL, an emulsifier used for formulation of water-insoluble drugs. Both the D 2O and KBr gradients provided similar results with regard to the affinity of anionic, neutral or cationic photosensitizers for LDL. The use of Cremophor EL for drug formulation was associated with an altered electrophoretic lipoprotein profile. In some cases, affinity of CRM-solubilized sensitizers for plasma components varied with the density-gradient employed. The high salt concentration used in density-gradient fractionation had little effect on the affinity of photosensitizing agents to low-density lipoprotein but may introduce artifacts when emulsifiers are used in drug formulation.

Effects of Cremophor EL on distribution of Taxol to serum lipoproteins

The clinical formulation of the anti-tumour agent Taxol involves the use of a mixture of ethanol and Cremophor EL. Gel electrophoresis and density-gradient ultracentrifugation were used to detect effects of Taxol infusions on serum lipoproteins. Use of the Cremophor vehicle results in a decrease in the electrophoretic mobility of serum lipoproteins along with the appearance of a lipoprotein dissociation product. These effects persist during a 24 h infusion and for at least 1.5 h afterwards, and can be reproduced in vitro using purified high-density lipoprotein (HDL) or low-density lipoprotein (LDL). In control serum, Taxol binds to albumin > HDL, but after serum is exposed to Cremophor EL in vitro or in vivo substantial binding of Taxol to the lipoprotein dissociation product(s) was observed. The latter could represent an important factor in taxol biodistribution.

Paclitaxel-induced cytotoxicity—the effects of cremophor EL (castor oil) on two human breast cancer cell lines with acquired multidrug resistant phenotype and induced expression of the permeability glycoprotein

Paclitaxel (Taxol ®) is a new cytotoxic agent with considerable activity in phase II studies on metastatic breast cancer. Paclitaxel for clinical use is dissolved in the solvents cremophor EL and ethanol. In this study, we added paclitaxel, formulated either in cremophor EL and ethanol or only in ethanol, in increasing concentrations to two parental human breast cancer cell lines (ZR 75-1 and HS 578T) and their corresponding sublines with acquired doxorubicin resistance and P-glycoprotein expression. Paclitaxel dissolved either in ethanol or ethanol plus cremophor EL, resulted in steep and almost identical dose-response curves for the parental lines ZR 75-1 and HS 578T, respectively, independent of the solvent used. When paclitaxel was formulated only in ethanol the effects on the corresponding doxorubicin-resistant sublines were significantly reduced compared with paclitaxel dissolved in ethanol plus cremophor EL. These effects by cremophor EL may partly explain some of the antitumoral effects observed by paclitaxel in anthracycline failing patients.

The effects of cremophor EL in the anaesthetized dog.

The effects of cremophor EL were studied in 13 anaesthetized, paralyzed and ventilated dogs. Twenty per cent cremophor EL in a dose of 4.3 +/- 0.92 ml was infused at a rate of 30 ml X hr-1. In seven dogs, thoracopulmonary compliance, heart rate, systemic arterial pressure (SAP), pulmonary pressures (PAP, PCWP, RAP), cardiac output (CO) and platelet and white cell counts, were measured before the injection of cremophor EL, at the end of infusion and 5, 10, 30 and 150 minutes after the end of infusion. In six dogs, SAP, CO, and blood volume were measured before the injection of cremophor EL, at the end of infusion and 10, 30, 90 and 150 minutes after the end of infusion. Plasma histamine and catecholamines were assayed before the injection of cremophor EL and 2, 5, 10, 30, 90 and 150 minutes after starting the infusion. Cremophor EL induced a marked, sustained and significant decrease in SAP at the end of infusion and at 5, 10 and 30 minutes after the completion of the infusion (-68, -71, -70 and -43 per cent respectively), in PCWP, RAP and CO (-78 per cent at the end of infusion, -32 per cent 150 minutes after the end of infusion). Heart rate and systemic vascular resistance did not vary significantly. Pulmonary vascular resistance increased at the end of infusion, five and ten minutes after the end of infusion (+734, +548 and +439 per cent respectively). Plasma volume decreased 10 and 30 minutes after the end of infusion (-28 and -30.5 per cent respectively).(ABSTRACT TRUNCATED AT 250 WORDS)