Disposition of Cremophor EL in humans limits the potential for modulation of the multidrug resistance phenotype in vivo.
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.
Department of Medical Oncology, Rotterdam Cancer Institute, University Hospital Rotterdam, The Netherlands. sparreboom@onch.azr.nl
A
A
Sparreboom
J
J
Verweij
M E
ME
van der Burg
W J
WJ
Loos
E
E
Brouwer
L
L
Viganò
A
A
Locatelli
A I
AI
de Vos
K
K
Nooter
G
G
Stoter
L
L
Gianni
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000502:physiology; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001825:Body Fluid Compartments; D002945:Cisplatin / Q000008:administration & dosage; D017321:Clinical Trials, Phase I as Topic; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple / Q000502:physiology*; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D006801:Humans; D007262:Infusions, Intravenous; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage / Q000627:therapeutic use; D010641:Phenotype; D013501:Surface-Active Agents / Q000493:pharmacokinetics*; D014018:Tissue Distribution
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D013501:Surface-Active Agents; C000515:cremophor EL; D004317:Doxorubicin; D017239:Paclitaxel; D005990:Glycerol; D002945:Cisplatin