Influence of PEPT2 on the Regional Distribution Kinetics of Cefadroxil in Brain Using Intracerebral Microdialysis in Rats, Wildtype and PEPT2 Knockout mice

Peptide transporter 2;Microdialysis;Cefadroxil;Blood-cerebrospinal fluid barrier;Health Sciences;Pharmaceutical Sciences

Chen, XiaomeiZhu, Haojie ;

University of Michigan

关键词: Peptide transporter 2;    Microdialysis;    Cefadroxil;    Blood-cerebrospinal fluid barrier;    Health Sciences;    Pharmaceutical Sciences;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/137151/xmchen_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Peptide transporter 2 (PEPT2) is a member of proton-coupled oligopeptide transporter (POT) family that recognizes and transports di-/tri-peptides and peptide-like drugs across cell membranes, thus playing an important role in substrate pharmacokinetics. In brain, PEPT2 works to efflux substrates from cerebrospinal fluid (CSF) into choroid plexus, thus limiting the substrate distribution in CSF. However, PEPT2 does not reduce the distribution of substrate in brain parenchyma, which is believed to be a more relevant site for the neurological effects of most compounds. Moreover, this finding is not consistent with the observance that PEPT2 decreases the neurological effects of its substrates (e.g., kyotorphin and 5-aminolevulinic acid). Considering that the brain parenchyma consists of extracellular fluid (ECF) and intracellular fluid (ICF), we hypothesized that PEPT2 has an impact in reducing substrate distribution in brain ECF, which is the site of neurological effects of most compounds. In the present study, intracerebral microdialysis (the only method to directly monitor drug concentrations in brain ECF) was applied to rats, wildtype and Pept2 knockout mice in order to study the impact of PEPT2 on the brain distribution of cefadroxil, a substrate of PEPT2 with high affinity. Our findings demonstrated that cefadroxil concentration in brain ECF of Pept2 knockout mice was 2.3 fold higher as compared to wildtype mice, indicating that PEPT2 as an efflux transporter at choroid plexus does not only reduce cefadroxil concentrations in CSF but also in brain ECF. Moreover, the microdialysis study of cefadroxil in rats (± probenecid) demonstrated that other transporters (e.g., OATs, MRPs and/or OATPs) were also involved in the elimination of cefadroxil from brain. PEPT2 also functions as an uptake transporter at brain cells (e.g., neurons in neonate and adult, and astrocytes in neonate), which resulted in a higher cefadroxil level in brain ICF compared to brain ECF (i.e., higher unbound volume distribution Vu,brain). These results provided significant insight into the mechanism by which PEPT2 affected the distribution of its substrates in brain (brain cells, ECF, and CSF) and could have important implications in the design and delivery of peptide-like pharmaceuticals for brain diseases.