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Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study.

Authors
  • Chen, Xiaomei1
  • Keep, Richard F2
  • Liang, Yan3
  • Zhu, Hao-Jie4
  • Hammarlund-Udenaes, Margareta5
  • Hu, Yongjun6
  • Smith, David E7
  • 1 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected]
  • 2 Department of Neurosurgery, University of Michigan Health System, Ann Arbor, MI, USA. Electronic address: [email protected]
  • 3 Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected]
  • 4 Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected]
  • 5 Department of Pharmaceutical Biosciences, Translational PKPD Research Group, Uppsala University, Uppsala, Sweden. Electronic address: [email protected] , (Sweden)
  • 6 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected]
  • 7 Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected]
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
May 01, 2017
Volume
131
Pages
89–97
Identifiers
DOI: 10.1016/j.bcp.2017.02.005
PMID: 28192085
Source
Medline
Keywords
License
Unknown

Abstract

Peptide transporter 2 (PEPT2) is a high-affinity low-capacity transporter belonging to the proton-coupled oligopeptide transporter family. Although many aspects of PEPT2 structure-function are known, including its localization in choroid plexus and neurons, its regional activity in brain, especially extracellular fluid (ECF), is uncertain. In this study, the pharmacokinetics and regional brain distribution of cefadroxil, a β-lactam antibiotic and PEPT2 substrate, were investigated in wildtype and Pept2 null mice using in vivo intracerebral microdialysis. Cefadroxil was infused intravenously over 4h at 0.15mg/min/kg, and samples obtained from plasma, brain ECF, cerebrospinal fluid (CSF) and brain tissue. A permeability-surface area experiment was also performed in which 0.15mg/min/kg cefadroxil was infused intravenously for 10min, and samples obtained from plasma and brain tissues. Our results showed that PEPT2 ablation significantly increased the brain ECF and CSF levels of cefadroxil (2- to 2.5-fold). In contrast, there were no significant differences between wildtype and Pept2 null mice in the amount of cefadroxil in brain cells. The unbound volume of distribution of cefadroxil in brain was 60% lower in Pept2 null mice indicating an uptake function for PEPT2 in brain cells. Finally, PEPT2 did not affect the influx clearance of cefadroxil, thereby, ruling out differences between the two genotypes in drug entry across the blood-brain barriers. These findings demonstrate, for the first time, the impact of PEPT2 on brain ECF as well as the known role of PEPT2 in removing peptide-like drugs, such as cefadroxil, from the CSF to blood.

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