title: Influence of peptide transporter 2 (PEPT2) on the distribution of cefadroxil in mouse brain: A microdialysis study.
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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: xmchen@umich.edu.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, University of Michigan Health System, Ann Arbor, MI, USA. Electronic address: rkeep@umich.edu.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Keep
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: liangyan0679@hotmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: hjzhu@med.umich.edu.
authors.forename: Hao-Jie
authors.initials: HJ
authors.lastname: Zhu
authors.affiliation: Department of Pharmaceutical Biosciences, Translational PKPD Research Group, Uppsala University, Uppsala, Sweden. Electronic address: mhu@farmbio.uu.se.
authors.forename: Margareta
authors.initials: M
authors.lastname: Hammarlund-Udenaes
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: yongjun@umich.edu.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA. Electronic address: smithb@umich.edu.
authors.forename: David E
authors.initials: DE
authors.lastname: Smith
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002434:Cefadroxil / Q000097:blood / Q000493:pharmacokinetics*; D051379:Mice; D018345:Mice, Knockout; D017551:Microdialysis; D027981:Symporters / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000900:Anti-Bacterial Agents; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D002434:Cefadroxil
keywords: Blood-cerebrospinal fluid barrier; Brain extracellular fluid; Cefadroxil; Microdialysis; Peptide transporter 2