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 4 hours at 0.15 mg/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 0.15 mg/min/kg cefadroxil was infused intravenously for 10 min, 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.

Brain-transportable dipeptides across the blood-brain barrier in mice

“…Hitherto, no influx carrier mechanism for peptide transport into brain parenchyma across the BBB has been elucidated. However, it has been reported that PepT2, expressed in the apical membrane of choroid plexus epithelial cells and plasma membrane of neural cells is involved in the removal of peptidic substrates from the CSF 32 . In this study, a significant reduction in the uptake of Gly-Sar by co-perfusion of His, a favorable PHT1 substrate 5 (Fig.…”

Revisiting atenolol as a low passive permeability marker

“…In addition, the unbound drug concentration in brain ECF rather than total concentration of drug in brain tissue is more relevant in understanding drug transport across BBB because the total concentration of drug is confounded by ECF-ICF and/or nonspecific binding equilibration (as characterized by V u,brain and f u,brain ). The conclusion about BBB transport based on total drug concentrations in brain could therefore be misleading [ 43 ]. Thus, the K p,uu,brain based on unbound concentration in plasma and brain ECF at steady state is a more clinically relevant measure to quantify drug transport at the BBB than rate measurements.…”

Identification of PEPT2 as an important candidate molecule in 5-ALA-mediated fluorescence-guided surgery in WHO grade II/III gliomas

“…In the central nervous system (CNS), PEPT2 can remove peptide/mimetic drugs from the cerebrospinal fluid to the plasma. PEPT2 is also responsible for the uptake of peptide/mimetic drugs from brain extracellular fluid into brain cells, which is important in regulating drug metabolism in the CNS [13][14][15]. PEPT2 protein consists of 729 amino acids, and the core molecular size is 81,940 Da.…”