Population pharmacokinetic modeling of cefadroxil renal transport in wild-type and Pept2 knockout mice

• Published in: Xenobiotica Vol. 46; no. 4; pp. 342 - 349
• Main Authors: Xie, Yehua, Shen, Hong, Hu, Yongjun, Feng, Meihua Rose, Smith, David E.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 02.04.2016
• Subjects: Administration, Intravenous; Animals; Biological Transport - drug effects; Cefadroxil - administration & dosage; Cefadroxil - pharmacokinetics; Disposition; kidney; Kidney - drug effects; Kidney - metabolism; mice; Mice, Knockout; Models, Biological; pharmacokinetics; Reproducibility of Results; Symporters - deficiency; Symporters - metabolism; transporters; Disposition; pharmacokinetics; kidney; transporters; mice
• ISSN: 0049-8254; 1366-5928
• DOI: 10.3109/00498254.2015.1080881

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 V 1 (3.43 versus 4.23 mL), volume of peripheral compartment V 2 (5.98 versus 8.61 mL), intercompartment clearance Q (0.599 versus 0.586 mL/min) and linear elimination rate constant K 10 (0.111 versus 0.070 min −1 ). Moreover, the secretion kinetics (i.e. V m 1  = 17.6 nmoL/min and K m 1  = 37.1 µM) and reabsorption kinetics (i.e. V m 2  = 15.0 nmoL/min and K m 2  = 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.