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 journalArticlepeer-review

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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