title: Incorporation of ABCB1-mediated transport into a physiologically-based pharmacokinetic model of docetaxel in mice.
abstract: Docetaxel is one of the most widely used anticancer agents. While this taxane has proven to be an effective chemotherapeutic drug, noteworthy challenges exist in relation to docetaxel administration due to the considerable interindividual variability in efficacy and toxicity associated with the use of this compound, largely attributable to differences between individuals in their ability to metabolize and eliminate docetaxel. Regarding the latter, the ATP-binding cassette transporter B1 (ABCB1, PGP, MDR1) is primarily responsible for docetaxel elimination. To further understand the role of ABCB1 in the biodistribution of docetaxel in mice, we utilized physiologically-based pharmacokinetic (PBPK) modeling that included ABCB1-mediated transport in relevant tissues. Transporter function was evaluated by studying docetaxel pharmacokinetics in wild-type FVB and Mdr1a/b constitutive knockout (KO) mice and incorporating this concentration-time data into a PBPK model comprised of eight tissue compartments (plasma, brain, heart, lung, kidney, intestine, liver and slowly perfused tissues) and, in addition to ABCB1-mediated transport, included intravenous drug administration, specific binding to intracellular tubulin, intestinal and hepatic metabolism, glomerular filtration and tubular reabsorption. For all tissues in both the FVB and KO cohorts, the PBPK model simulations closely mirrored the observed data. Furthermore, both models predicted AUC values that were with 15 % of the observed AUC values, indicating that our model-simulated drug exposures accurately reflected the observed tissue exposures. Overall, our PBPK model furthers the understanding of the role of ABCB1 in the biodistribution of docetaxel. Additionally, this exemplary model structure can be applied to investigate the pharmacokinetics of other ABCB1 transporter substrates.
authors.affiliation: Department of Clinical Sciences, Flint Animal Cancer Center, Colorado State University, 1678 Campus Delivery, Fort Collins, CO 80523, USA. susanhudachek@gmail.com
authors.forename: Susan F
authors.initials: SF
authors.lastname: Hudachek
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D061605:Administration, Intravenous; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001692:Biological Transport; D000077143:Docetaxel; D005260:Female; D005919:Glomerular Filtration Rate; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D043823:Taxoids / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D014404:Tubulin / Q000378:metabolism
chemical_list: D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D043823:Taxoids; D014404:Tubulin; D000077143:Docetaxel