Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.3.44 (P-glycoprotein)
13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The purpose of the present study was to characterize the distribution and elimination kinetics of the paclitaxel vehicle Cremophor EL (CrEL), a polyoxyethylated castor oil that can modulate P-glycoprotein-mediated multidrug resistance in vitro. The pharmacokinetics of CrEL were studied using noncompartmental models in 23 patients with histological proof of malignant solid tumors, receiving paclitaxel as a 3-h i.v. infusion at dose levels ranging from 100-225 mg/m2 (corresponding to CrEL doses of 8.33-18.8 ml/m2). Serial plasma samples were obtained before and up to 72 h after drug administration, and were analyzed for the presence of CrEL by a novel colorimetric dye-binding microassay. The area under the plasma concentration versus time curves and the peak plasma levels of CrEL increased from 253+/-36.8 (mean+/-SD) to 680+/- 180 microl.h/ml, and from 3.40+/-0.10 to 6.58+/-0.52 microl/ml, respectively, consistent with linear pharmacokinetics. Disappearance of CrEL from the central plasma compartment was characterized by a terminal elimination half-life of 84.1+/-20.4 h, resulting in extended persistence of substantial levels even at 1 week after paclitaxel treatment. The observed volume of distribution was extremely low and averaged 3.70+/-0.49 liters/m2, implying that the tumor delivery of CrEL is insignificant. Our results indicate that CrEL is a relatively slow clearance compound and that its distribution is limited to the central plasma compartment. Hence, CrEL is not likely to play a role in reversing P-glycoprotein-mediated multidrug resistance to paclitaxel in vivo.
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PMID:Disposition of Cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. 971 22

Cremophor EL (cremophor), a component of the paclitaxel formulation, can potentially reverse P-glycoprotein-associated multidrug resistance. A Phase I trial of cremophor as a 6-h infusion every 3 weeks was performed with bolus doxorubicin (50 mg/m2). The cremophor dose was escalated from 1 to 60 ml/m2. A standard paclitaxel premedication was given before cremophor. Using a bioassay, potentially active cremophor levels (> or = 1 microl/ml) were measured in plasma from patients receiving cremophor doses of 30, 45, and 60 ml/m2. A cross-over design was used to assess the influence of cremophor 30 ml/m2 on the pharmacokinetics of doxorubicin and doxorubicinol. The plasma area under the concentration versus time curve (AUC) of doxorubicin increased from 1448 +/- 350 to 1786 +/- 264 ng/ml x h (P = 0.02) in the presence of cremophor, whereas the AUC of doxorubicinol increased from 252 +/- 104 to 486 +/- 107 ng/ml x h (P = 0.02). This pharmacokinetic interaction was associated with significantly increased neutropenia. With reduction of the doxorubicin dose to 35 mg/m2, the cremophor dose was increased to 60 ml/m2. Dose-limiting toxicities occurred in two of six patients after 45 ml/m2 and two of four patients after 60 ml/m2, which included febrile neutropenia and grade III cremophor-related toxicities of rash, pruritus, headache, and hypotension. All patients who received 45 ml/m2 cremophor reached plasma levels > or = 1.5 microl/ml, but at 60 ml/m2, only two of four reached this level, and the calculated plasma clearance of cremophor was significantly faster at this dose. One patient with hepatoma resistant to epirubicin achieved a near-complete response. Cremophor 45 ml/m2 over 6 h with 35 mg/m2 doxorubicin is recommended for further studies. The pharmacokinetic interaction between cremophor and doxorubicin is quantitatively similar to that described in trials of paclitaxel with doxorubicin and suggests that the cremophor in the paclitaxel formulation is responsible.
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PMID:Phase I trial of cremophor EL with bolus doxorubicin. 979 61

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.
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PMID:Effect of Cremophor EL on the pharmacokinetics, antitumor activity and toxicity of doxorubicin in mice. 984 Jul 28

Paclitaxel is currently formulated in a vehicle of 50% ethanol and 50% polyethoxylated surfactant cremophor EL. Cremophor EL has been reported to reverse P-glycoprotein-mediated multidrug resistance (MDR) at doses which are clinically achievable. It has also been reported to have a cytotoxic effect per se. In this study we used two different methods to evaluate the survival of cells exposed to paclitaxel with or without cremophor EL and the vehicle alone. Two laryngeal SCC cell lines (UT-SCC-19A and UT-SCC-29) and two ovarian adenocarcinoma cell lines (UT-OC-3 and UT-OC-5) established in our laboratory were investigated. Northern hybridisation was used to study the mdr-1 mRNA expression of the cell lines. With sensitive Northern analyses, these four lines yielded mdr-1 mRNA signals of the expected 4.5 kb size and of variable intensity, generally at higher levels than those in the positive control cell line KB. The 96-well plate clonogenic assay was used to obtain the fraction survival data and apoptosis was recorded by time-lapse video microscopy. Both methods indicate that cremophor EL alone has no effect on cellular survival. Consequently, paclitaxel without cremophor EL is as active as paclitaxel with cremophor EL in vitro.
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PMID:Effects of paclitaxel with or without cremophor EL on cellular clonogenic survival and apoptosis. 1044 72

i.v. paclitaxel is inconvenient and associated with significant and poorly predictable side effects largely due to the pharmaceutical vehicle Cremophor EL. Oral administration may be attractive because it may circumvent the use of Cremophor EL. However, paclitaxel, as well as many other commonly applied drugs, has poor bioavailability caused by high affinity for the mdrl P-glycoprotein drug efflux pump, which is abundantly present in the gastrointestinal tract. Consequently, inhibition of P-glycoprotein by oral cyclosporin A (CsA) should increase systemic exposure of oral paclitaxel to therapeutic levels. A proof-of-concept study was carried out in 14 patients with solid tumors. Patients received one course of oral paclitaxel of 60 mg/m2 with or without 15 mg/kg CsA and with i.v. paclitaxel in subsequent courses. The pharmacokinetics of paclitaxel and its major metabolites were determined during the first two courses. In addition, levels of CsA, Cremophor EL, and ethanol were measured. Bioavailability of oral paclitaxel in combination with CsA was 8-fold higher than after oral paclitaxel alone (P<0.001). Therapeutic concentrations were achieved on average during 7.4 h, which is comparable with an equivalent i.v. dose. The oral combination was well tolerated and did not induce gastrointestinal toxicity or myelosuppression. Cremophor EL plasma levels after oral drug administration were undetectable. In conclusion, coadministration of oral CsA increased the systemic exposure of oral paclitaxel from negligible to therapeutic levels. The combination enables treatment with oral paclitaxel. Undetectable Cremophor EL levels after oral administration may have a very beneficial influence on the safety of the treatment with oral paclitaxel.
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PMID:Coadministration of oral cyclosporin A enables oral therapy with paclitaxel. 1058 48

Surfactants are classically used to improve the solubilization of lipophilic drugs such as digoxin. Polysorbate 80 and Cremophor EL (polyoxyl 35 castor oil) are such surfactants but they may also modulate the action of P-glycoprotein, an energy-dependent "counter-transport" system implicated in the phenomenon of multidrug resistance in cancer cells. P-glycoprotein is also present in the intestine on the apical membrane of mature enterocytes and can potentially reduce the absorption of a wide range of drugs. In this study, using the improved everted gut sac method, the effects of Polysorbate 80, Cremophor EL and cyclosporin on the absorption of digoxin were studied. An increase in the uptake of digoxin in the presence of these three products could be shown with our in vitro model. Cremophor EL and Polysorbate 80 had no toxic effects at the concentrations used. These results suggest that surfactants such as Cremophor EL and Polysorbate 80 should not only support solubilization but can also modulate the P-glycoprotein system to improve the bioavailability of poorly absorbed drugs.
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PMID:Effect of polyoxyl 35 castor oil and Polysorbate 80 on the intestinal absorption of digoxin in vitro. 1091 54

We compared the effects of paclitaxel (Taxol) in human renal cell carcinoma (RCC) of different histologic types. The growth inhibitory effects of paclitaxel on 34 human RCC cell lines of strictly defined different histologic types were determined by 3-[4,5-dimethylthiazolyl]-2,5-diphenyltetrazoliumbromide (MTT) assays. Paclitaxel-induced morphologic alterations were visualized by light and immunofluorescence and by transmission electron microscopy. The expression and function of P-glycoprotein and multidrug resistance-associated protein (MRP) were defined by reverse transcriptase polymerase chain reaction and fluorescence-activated cell sorting (FACS) analysis, respectively. Modulation of P-glycoprotein function was performed by verapamil or Cremophor EL. A significant (p < 0.05) dose-dependent paclitaxel-induced growth inhibition could be demonstrated in all cell lines, with the effects of paclitaxel dissolved in Cremophor EL/ethanol (= Taxol) exceeding the effects of paclitaxel dissolved in dimethyl sulfoxide. The extent of response markedly varied between the different cell lines, although chromophilic RCCs exhibited a more pronounced response to Taxol (IC50: 0.03-0.38 microM) than clear cell RCCs (IC50: 0.01-36.69 microM). Exposure to paclitaxel/Taxol induced an increase of microtubule bundles in the clear cell and the chromophobe RCCs but not in the chromophilic RCCs. The expression of the MRP was low in RCC cell lines and was not found to be related to paclitaxel/Taxol sensitivity. In contrast, the expression level of P-glycoprotein was much more pronounced and showed a positive correlation (p < 0.05) with the response to paclitaxel. Reversal of P-glycoprotein function by verapamil or Cremophor EL enhanced the growth inhibitory effects of paclitaxel and further supported the role of P-glycoprotein for paclitaxel sensitivity of human RCCs. Paclitaxel/Taxol effectively inhibits proliferation of human RCCs in vitro, irrespective of their histologic types. Moreover, expression and function of P-glycoprotein markedly contribute to paclitaxel responsiveness, although other as yet undefined drug resistance mechanisms are effective in human RCCs as well.
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PMID:Multidrug resistance phenotype and paclitaxel (Taxol) sensitivity in human renal carcinoma cell lines of different histologic types. 1103 69

The application of most agents with the capacity to reverse multidrug resistance (MDR) via modulation of the multidrug transporter P-glycoprotein (Pgp) was shown to be associated with toxic side-effects. For this reason, we have investigated the effect of combinations of suboptimal concentrations of Pgp blockers on the induction of apoptosis and growth arrest in daunorubicin (D) treated, MDR1 gene transfected cells. We used verapamil, PSC833 and Cremophor EL as Pgp modulators, which affect the function of Pgp by different mechanisms. Treatment of NIH3T3/MDR1 cells with combinations of suboptimal concentrations of Pgp modulators in the presence of D caused apoptosis and G(2) arrest to the same extent as optimal concentrations of singly used blockers. We conclude that combinations of suboptimal concentrations of Pgp modulators may cause effective sensitization of resistant tumor cells, and at the same time, may avoid the frequently observed toxic effects experienced in clinical trials with a single modifier applied at the optimal dose.
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PMID:Induction of apoptosis in MDR1 expressing cells by daunorubicin with combinations of suboptimal concentrations of P-glycoprotein modulators. 1136 36

The non-ionic surfactants Cremophor EL (CrEL) and Tween 80, both used as formulation vehicles of many (anticancer) agents including paclitaxel and docetaxel, are not physiological inert compounds. We describe their biological properties, especially the toxic side effects, and their pharmacological properties, such as modulation of P-glycoprotein activity. In detail, we discuss their influence on the disposition of the solubilized drugs, with focus on CrEL and paclitaxel, and of concomitantly administered drugs. The ability of the surfactants to form micelles in aqueous solution as well as biological fluids (e.g. plasma) appears to be of great importance with respect to the pharmacokinetic behavior of the formulated drugs. Due to drug entrapment in the micelles, plasma concentrations and clearance of free drug change significant leading to alteration in pharmacodynamic characteristics. We conclude with some perspectives related to further investigation and development of alternative methods of administration.
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PMID:Role of formulation vehicles in taxane pharmacology. 1139 47

Recombinant rIL-2 was reported to be able to decrease P-glycoprotein (P-gp) expression in cultured cells from human colon carcinoma. P-gp is considered an important factor in the control of Taxol efflux from tumor cells. Based on the premise that Taxol pharmacokinetic parameters could be modified as a result of diminished P-gp expression induced by recombinant interleukin (rIL)-2 and that this might elicit an interaction between the two drugs, we evaluated the pharmacokinetics of a novel strategy combining i.p. immunotherapy with rIL-2 and a cytotoxic agent, Taxol. Mice were allocated to two groups treated with rIL-2 (15 microg x 2/day from day 1 to 4) then Taxol (10 mg/kg i.p. day 5) or Taxol (10 mg/kg i.p.) alone (control group). The Taxol + rIL-2 combination provoked the development of ascites, presumably due to the presence of Cremophor EL in the Taxol preparation. Paclitaxel was measured in plasma and ascites by HPLC with UV detection. Paclitaxel pharmacokinetics were strongly modified by rIL-2 pretreatment. Compared to that observed in control mice, the apparent volume of distribution increased dramatically (Vd/F = 18.2 versus 4.1 l/kg) and the apparent plasma clearance decreased (Cl/F = 1.12 versus 1.66 l/h/kg). P-gp expression was determined in the liver, lung, intestine, brain and kidney in the two groups by immunodetection with the C219 anti-P-gp monoclonal antibody. A significant decrease in P-gp expression was observed in the intestine and in the brain in the rIL-2-pretreated mice as compared to controls. To study the functionality of P-gp, we compared digoxin (a model P-gp substrate) pharmacokinetics before and after pretreatment with rIL-2 (10 microg x 2/day from day 1 to 4), after a single 1 microg oral dose of digoxin used to quantify P-gp activity. Results showed a decrease in oral digoxin clearance after rIL-2 pretreatment indicating modified P-gp activity. We conclude that rIL-2 pretreatment is able to decrease P-gp activity and paclitaxel metabolism in vivo. This is the first study to demonstrate a decrease in P-gp activity and expression in organs such as the brain in vivo. A novel strategy combining immunotherapy with rIL-2 and a cytotoxic agent could potentially improve clinical results, particularly in brain cancer.
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PMID:Recombinant interleukin-2 treatment decreases P-glycoprotein activity and paclitaxel metabolism in mice. 1191 41


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