title: Population pharmacokinetic modeling of cefadroxil renal transport in wild-type and Pept2 knockout mice.
abstract: 1. Cefadroxil is a broad-spectrum β-lactam antibiotic that is widely used in the treatment of various infectious diseases. Currently, poor understanding of the drug's pharmacokinetic profiles and disposition mechanism(s) prevents determining optimal dosage regimens and achieving ideal antibacterial responses in patients. In the present retrospective study, we developed a population pharmacokinetic model of cefadroxil in wild-type and Pept2 knockout mice using the nonlinear mixed effect modeling (NONMEM) approach. 2. Cefadroxil pharmacokinetics were best described by a two-compartment model, with both saturable and nonsaturable elimination processes to/from the central compartment. Through this modeling approach, pharmacokinetic parameters in wild-type and Pept2 knockout mice were well estimated, respectively, as follows: volume of central compartment V1 (3.43 versus 4.23 mL), volume of peripheral compartment V2 (5.98 versus 8.61 mL), intercompartment clearance Q (0.599 versus 0.586 mL/min) and linear elimination rate constant K10 (0.111 versus 0.070 min(-1)). Moreover, the secretion kinetics (i.e. V(m1) = 17.6 nmoL/min and K(m1) = 37.1 µM) and reabsorption kinetics (i.e. V(m2) = 15.0 nmoL/min and K(m2) = 27.1 µM) of cefadroxil were quantified in kidney, for the first time, under in vivo conditions. 3. Our model provides a unique tool to quantitatively predict the dose-dependent nonlinear disposition of cefadroxil, as well as the potential for transporter-mediated drug interactions.
authors.affiliation: a Department of Pharmaceutical Sciences , College of Pharmacy, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Yehua
authors.initials: Y
authors.lastname: Xie
authors.affiliation: a Department of Pharmaceutical Sciences , College of Pharmacy, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Shen
authors.affiliation: a Department of Pharmaceutical Sciences , College of Pharmacy, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Hu
authors.affiliation: a Department of Pharmaceutical Sciences , College of Pharmacy, University of Michigan , Ann Arbor , MI , USA.
authors.forename: Meihua Rose
authors.initials: MR
authors.lastname: Feng
authors.affiliation: a Department of Pharmaceutical Sciences , College of Pharmacy, University of Michigan , Ann Arbor , MI , USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002434:Cefadroxil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D008954:Models, Biological; D015203:Reproducibility of Results; D027981:Symporters / Q000172:deficiency* / Q000378:metabolism
chemical_list: D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D002434:Cefadroxil
keywords: Disposition; kidney; mice; pharmacokinetics; transporters