Distribution of glycylsarcosine and cefadroxil among cerebrospinal fluid, choroid plexus, and brain parenchyma after intracerebroventricular injection is markedly different between wild-type and Pept2 null mice.
The purpose of this study was to define the cerebrospinal fluid (CSF) clearance kinetics, choroid plexus uptake, and parenchymal penetration of PEPT2 substrates in different regions of the brain after intracerebroventricular administration. To accomplish these objectives, we performed biodistribution studies using [(14)C]glycylsarcosine (GlySar) and [(3)H]cefadroxil, along with quantitative autoradiography of [(14)C]GlySar, in wild-type and Pept2 null mice. We found that PEPT2 deletion markedly reduced the uptake of GlySar and cefadroxil in choroid plexuses at 60 mins by 94% and 82% (P<0.001), respectively, and lowered their CSF clearances by about fourfold. Autoradiography showed that GlySar concentrations in the lateral, third, and fourth ventricle choroid plexuses were higher in wild-type as compared with Pept2 null mice (P<0.01). Uptake of GlySar by the ependymal-subependymal layer and septal region was higher in wild-type than in null mice, but the half-distance of penetration into parenchyma was significantly less in wild-type mice. The latter is probably because of the clearance of GlySar from interstitial fluid by brain cells expressing PEPT2, which stops further penetration. These studies show that PEPT2 knockout can significantly modify the spatial distribution of GlySar and cefadroxil (and presumably other peptides/mimetics and peptide-like drugs) in brain.
Smith
David E
DE
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-5633, USA. smithb@umich.edu
Hu
Yongjun
Y
Shen
Hong
H
Nagaraja
Tavarekere N
TN
Fenstermacher
Joseph D
JD
Keep
Richard F
RF
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001345:Autoradiography; D001921:Brain / Q000378:metabolism*; D002434:Cefadroxil / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D002831:Choroid Plexus / Q000378:metabolism*; D004151:Dipeptides / Q000008:administration & dosage / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D006207:Half-Life; D007091:Image Processing, Computer-Assisted; D007276:Injections, Intraventricular; D008353:Mannitol / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027981:Symporters / Q000235:genetics* / Q000378:metabolism*
D000900:Anti-Bacterial Agents; D004151:Dipeptides; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D002434:Cefadroxil; C004194:glycylsarcosine; D008353:Mannitol