title: Kinetics of P-glycoprotein-mediated efflux of paclitaxel.
abstract: Paclitaxel is a substrate of the mdr1 P-glycoprotein (Pgp). The objective of the present study was to determine the kinetics of the Pgp-mediated efflux and its contribution to the overall efflux of paclitaxel at the clinically achievable concentration range of 1 to 1500 nM. Human breast carcinoma BC19 cells that were derived from MCF7 cells by mdr1 transfection and show a >10-fold higher level of the Pgp protein were used to measure the uptake and efflux of [(3)H]paclitaxel. A computational model of intracellular paclitaxel pharmacokinetics was developed to analyze for the Pgp efflux parameters. The results show a saturable Pgp-mediated efflux in BC19 cells; the dissociation constant was 14 nM, and the maximal efflux rate was 2.8 x 10(-4) pmol/h/cell. The contribution of Pgp-mediated efflux to the total efflux decreased with increasing extracellular drug concentrations; the Pgp efflux accounted for 86 and 34% of total efflux at 1 and 1500 nM, respectively. The validity of the model was confirmed by the close agreement between the model-predicted data and the experimentally obtained data (approximately 6% deviation) describing the effect of cell density and intracellular-to-extracellular concentration gradient on the kinetics of drug accumulation and efflux. In conclusion, our results indicate that the Pgp-mediated efflux represents a major efflux mechanism of paclitaxel at the low end of the clinically observed drug concentration range, but accounts for only a minor part of the efflux at higher concentrations in BC19 cells.
authors.affiliation: College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Jang
authors.forename: M G
authors.initials: MG
authors.lastname: Wientjes
authors.forename: J L
authors.initials: JL
authors.lastname: Au
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000378:metabolism; D005260:Female; D019450:Genes, MDR / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D017239:Paclitaxel / Q000493:pharmacokinetics*; D015203:Reproducibility of Results; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel