Disposition of cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo

Alex Sparreboom, Jaap Verweij, Maria E L Van Der Burg, Walter J. Loos, Eric Brouwer, Lucia Viganò, Alberta Locatelli, Aad I. De Vos, Kees Nooter, Gerrit Stoter, Luca Gianni

Research output: Contribution to journalArticle

Abstract

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 μl·h/ml, and from 3.40 ± 0.10 to 6.58 ± 0.52 μl/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.

Original languageEnglish
Pages (from-to)1937-1942
Number of pages6
JournalClinical Cancer Research
Volume4
Issue number8
Publication statusPublished - Aug 1998

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Multiple Drug Resistance
Phenotype
Paclitaxel
P-Glycoprotein
Pharmacokinetics
Castor Oil
cremophor EL
Half-Life
Neoplasms
Coloring Agents

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Sparreboom, A., Verweij, J., Van Der Burg, M. E. L., Loos, W. J., Brouwer, E., Viganò, L., ... Gianni, L. (1998). Disposition of cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. Clinical Cancer Research, 4(8), 1937-1942.

Disposition of cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. / Sparreboom, Alex; Verweij, Jaap; Van Der Burg, Maria E L; Loos, Walter J.; Brouwer, Eric; Viganò, Lucia; Locatelli, Alberta; De Vos, Aad I.; Nooter, Kees; Stoter, Gerrit; Gianni, Luca.

In: Clinical Cancer Research, Vol. 4, No. 8, 08.1998, p. 1937-1942.

Research output: Contribution to journalArticle

Sparreboom, A, Verweij, J, Van Der Burg, MEL, Loos, WJ, Brouwer, E, Viganò, L, Locatelli, A, De Vos, AI, Nooter, K, Stoter, G & Gianni, L 1998, 'Disposition of cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo', Clinical Cancer Research, vol. 4, no. 8, pp. 1937-1942.
Sparreboom A, Verweij J, Van Der Burg MEL, Loos WJ, Brouwer E, Viganò L et al. Disposition of cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. Clinical Cancer Research. 1998 Aug;4(8):1937-1942.
Sparreboom, Alex ; Verweij, Jaap ; Van Der Burg, Maria E L ; Loos, Walter J. ; Brouwer, Eric ; Viganò, Lucia ; Locatelli, Alberta ; De Vos, Aad I. ; Nooter, Kees ; Stoter, Gerrit ; Gianni, Luca. / Disposition of cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo. In: Clinical Cancer Research. 1998 ; Vol. 4, No. 8. pp. 1937-1942.
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