Influence of Cremophor EL and genetic polymorphisms on the pharmacokinetics of paclitaxel and its metabolites using a mechanism-based model.
The formulation vehicle Cremophor EL has previously been shown to affect paclitaxel kinetics, but it is not known whether it also affects the kinetics of paclitaxel metabolites. This information may be important for understanding paclitaxel metabolism in vivo and in the investigation of the role of genetic polymorphisms in the metabolizing enzymes CYP2C8 and CYP3A4/CYP3A5 and the ABCB1 transporter. In this study we used the population pharmacokinetic approach to explore the influence of predicted Cremophor EL concentrations on paclitaxel (Taxol) metabolites. In addition, correlations between genetic polymorphisms and enzyme activity with clearance of paclitaxel, its two primary metabolites, 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel, and its secondary metabolite, 6α-p-3'-dihydroxypaclitaxel were investigated. Model building was based on 1156 samples from a study with 33 women undergoing paclitaxel treatment for gynecological cancer. Total concentrations of paclitaxel were fitted to a model described previously. One-compartment models characterized unbound metabolite concentrations. Total concentrations of 6α-hydroxypaclitaxel and p-3'-hydroxypaclitaxel were strongly dependent on predicted Cremophor EL concentrations, but this association was not found for 6α-p-3'-dihydroxypaclitaxel. Clearance of 6α-hydroxypaclitaxel (fraction metabolized) was significantly correlated (p < 0.05) to the ABCB1 allele G2677T/A. Individuals carrying the polymorphisms G/A (n = 3) or G/G (n = 5) showed a 30% increase, whereas individuals with polymorphism T/T (n = 8) showed a 27% decrease relative to those with the polymorphism G/T (n = 17). The correlation of G2677T/A with 6α-hydroxypaclitaxel has not been described previously but supports other findings of the ABCB1 transporter playing a part in paclitaxel metabolism.
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. martin.fransson@ki.se
Martin N
MN
Fransson
Henrik
H
Gréen
Jan-Eric
JE
Litton
Lena E
LE
Friberg
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000704:Analysis of Variance; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D001711:Biotransformation / Q000187:drug effects / Q000235:genetics; D002626:Chemistry, Pharmaceutical; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D005990:Glycerol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008875:Middle Aged; D008954:Models, Biological; D017239:Paclitaxel / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; C000515:cremophor EL; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; C510164:CYP3A5 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017239:Paclitaxel; D005990:Glycerol