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

• Published in: Clinical cancer research 1998-08, Vol.4 (8), p.1937-1942
• Main Authors: SPARREBOOM, A, VERWEIJ, J, GIANNI, L, VAN DER BURG, M. E. L, LOOS, W. J, BROUWER, E, VIGANO, L, LOCATELLI, A, DE VOS, A. I, NOOTER, K, STOTER, G
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Biological and medical sciences; Body Fluid Compartments; Chemotherapy; Cisplatin - administration & dosage; Clinical Trials, Phase I as Topic; Doxorubicin - administration & dosage; Drug Resistance, Multiple - physiology; Female; Glycerol - analogs & derivatives; Glycerol - blood; Glycerol - pharmacokinetics; Humans; Infusions, Intravenous; Medical sciences; Middle Aged; Neoplasms - blood; Neoplasms - drug therapy; Neoplasms - metabolism; Paclitaxel - administration & dosage; Paclitaxel - therapeutic use; Pharmacology. Drug treatments; Phenotype; Surface-Active Agents - pharmacokinetics; Tissue Distribution
• ISSN: 1078-0432; 1557-3265

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.