Quantitation of Cremophor EL in Human Plasma Samples Using a Colorimetric Dye-Binding Microassay

Sparreboom, Alex; Loos, Walter J.; Verweij, Jaap; Vos, Aad I. de; Burg, M.E.L. van der; Stoter, G.; Nooter, Kees

doi:10.1006/abio.1997.2467

Cited by 47 publications

(33 citation statements)

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“…Our results are in line with those found using a colorimetric assay for Cremophor EL described very recently (Sparreboom et al, 1998a(Sparreboom et al, , 1998b. Although these authors studied the pharmacokinetics over a wide dose range (100-225 mg m -2 ) using 3-h i.v.…”

Section: Discussionsupporting

confidence: 93%

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

et al. 1999

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Paclitaxel (Taxol) is a potent anticancer drug with proven activity against a number of human solid tumours, including ovarian and breast, non-small-cell lung, and head and neck cancer (Huizing et al, 1995a;Rowinsky et al, 1995). Because of its poor water solubility the drug is formulated in a mixture of polyoxyethyleneglycerol triricinoleate 35 (Cremophor EL) and dehydrated ethanol USP (1:1, v/v; Taxol®). Prior to intravenous (i.v.) administration the drug solution is diluted 5-to 20-fold with saline or 5% dextrose. Patients receiving therapeutic dosages (e.g. 175 mg m -2 ) of paclitaxel (Taxol) receive about 25 ml of Cremophor EL solvent. The non-linear pharmacokinetic behaviour of paclitaxel in patients has been well documented (Huizing et al, 1993;Sonnichsen et al, 1994;Gianni et al, 1995;Kearns et al, 1995;Huizing et al, 1997). Both a reduction in the clearance and an over proportional increase in peak plasma concentration (C max ) of paclitaxel are observed with increasing dosages indicative that both drug elimination and distribution were affected. We have recently shown that the non-linear pharmacokinetics of paclitaxel in mice results from Cremophor EL exclusively, since linear plasma pharmacokinetics occurred when the same dose levels of paclitaxel were administered in a Cremophor EL free drug formulation (Sparreboom et al, 1996b). In patients, administration of paclitaxel in a Cremophor EL free formulation to test if the pharmacokinetics becomes linear is not a feasible option. Indirectly, however, our observations support the idea that Cremophor EL may also be responsible for the non-linear pharmacokinetics in patients provided that the plasma levels of Cremophor EL are in the same range as those observed in mice.In mice, the plasma concentrations of Cremophor EL as established by high-performance liquid chromatography (HPLC) ranged from 0.3 to 2.1% (Sparreboom et al, 1996b). Information on the pharmacokinetics of Cremophor EL in patients is limited. A previous paper using a bio-assay reported Cremophor EL levels up to 0.2% (Webster et al, 1993;Rischin et al, 1996). However, our preliminary information using the HPLC assay has revealed that the Cremophor EL levels are much higher (Sparreboom et al, 1996b;Van Tellingen et al, 1996). To address the issue if Cremophor EL can also be held responsible for the non-linear pharmacokinetics in patients, we have established the pharmacokinetic behaviour of this excipient in patients receiving 135 or 175 mg m -2 of paclitaxel (Taxol) by 3-or 24-h infusions. Because we have previously suggested that alterations in the affinity of paclitaxel toward plasma components might provide an explanation for the nonlinear plasma pharmacokinetics (Sparreboom et al, 1996b), we have now used an in vitro equilibrium dialysis assay and determination of paclitaxel in plasma ultrafiltrate to assess the influence of Cremophor EL on plasma binding of paclitaxel. PATIENTS AND METHODS PatientsThe patients included in this study received paclitaxel formulated in Cremophor EL:Ethanol 1...

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Section: Discussionsupporting

confidence: 93%

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

et al. 1999

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“…26 The samples were analyzed in duplicate with a standard curve ranging from 0.1 to 1.0% and a spiked quality control sample. The sample concentration was interpolated from the nonlinear standard curve by second-order polynominal regression using GraphPad Prism version 5.0a (GraphPad software, La Jolla, CA, USA).…”

Section: Patientsmentioning

confidence: 99%

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

et al. 2010

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The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h -1 (range 176-726 l h -1 ). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P ¼ 0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P ¼ 0.04) and ABCC1 g.7356253C4G (P ¼ 0.04).

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“…Castor oil is obtained from the seeds of Ricinus communis (Euphorbiaceae) and consists primarily of the triglycerides of ricinoleic, isoricinoleic, stearic, and dihydroxystearic acids (1).…”

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confidence: 99%

“…Due to its detergent properties, CrEL has been widely used to solubilize waterinsoluble drugs such as anesthetics (1), antineoplastic agents (1,2), immunosuppressive agents (3), analgesics (4,5), vitamins (6), and new synthetic water-insoluble compounds. Although in general CrEL is considered relatively nontoxic (1,7), several reports have suggested that drugs administered in CrEL induce serious complications like anaphylactoid hypersensitivity (6) and axonal swelling, degeneration and demyelination (2,3).…”

mentioning

confidence: 99%

“…Although in general CrEL is considered relatively nontoxic (1,7), several reports have suggested that drugs administered in CrEL induce serious complications like anaphylactoid hypersensitivity (6) and axonal swelling, degeneration and demyelination (2,3). Moreover, it has been proposed that CrEL plays a role in the etiology of the peripheral neuropathy observed after intravenous paclitaxel (2) or cyclosporin A treatment (3), and recent evidence supports the notion that CrEL affects nerve conduction (2,8).…”

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confidence: 99%

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Antinociceptive effects of Cremophor EL orally administered to mice

Tabarelli

Berlese

et al. 2003

Braz J Med Biol Res

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Surfactants are frequently used to improve solubilization of lipophilic drugs. Cremophor EL (CrEL) is a polyoxyethylated castor oil surfactant used to solubilize water-insoluble drugs such as anesthetic, antineoplastic, immunosuppressive and analgesic drugs, vitamins and new synthetic compounds, including potential analgesics. The antinociceptive effect of CrEL (3.2, 6.4 and 10.6 g/kg, in 10 ml/kg body weight, by gavage) on the abdominal writhing response induced by intraperitoneal administration of acetic acid (0.8%, 10 ml/kg body weight) and on the tail immersion test was investigated in mice. Control animals received castor oil (10 ml/kg body weight) or saline (0.9% NaCl, 10 ml/kg body weight). CrEL reduced nociception in a dose-dependent manner in both tests. At 10.6 g/kg, CrEL caused antinociception similar to that induced by dipyrone (300 mg/kg, by gavage) in the abdominal writhing test, and antinociception similar to that induced by morphine (20 mg/kg, by gavage) in the tail immersion test. The effect of castor oil was similar to that of saline in both assays. These data indicate that the appropriate controls should be used when evaluating the effects of potential antinociceptive agents dissolved in CrEL.

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Quantitation of Cremophor EL in Human Plasma Samples Using a Colorimetric Dye-Binding Microassay

Cited by 47 publications

References 15 publications

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

Cremophor EL causes (pseudo-) non-linear pharmacokinetics of paclitaxel in patients

Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer

Antinociceptive effects of Cremophor EL orally administered to mice

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