期刊
DRUG METABOLISM AND PHARMACOKINETICS
卷 23, 期 4, 页码 236-242出版社
JAPANESE SOC STUDY XENOBIOTICS
DOI: 10.2133/dmpk.23.236
关键词
PEPT2; knockout mice; glycylsarcosine; cefadroxil; 5-aminolevulinic acid; disposition; dynamics; toxicity
资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [P01HL018575] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM007767, R01GM035498] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS034709] Funding Source: NIH RePORTER
- NHLBI NIH HHS [P01 HL018575] Funding Source: Medline
- NIGMS NIH HHS [R01 GM035498-15, R01 GM035498, T32 GM007767] Funding Source: Medline
- NINDS NIH HHS [R01 NS034709] Funding Source: Medline
Pept2 knockout mice are an important tool to evaluate the evolving role and relevance of this proton-coupled oligopeptide transporter beyond drug disposition, where the transporter also modulates the pharmacodynamic and toxicodynamic effects of drug substrates. Our in vivo studies with glycylsarcosine in Pept2 knockout mice have established proof of concept'' that PEPT2 can have a significant effect on dipeptide disposition. Subsequent studies with the aminocephalosporin antibiotic cefadroxil have shown relevance to pharmacology and infectious disease. Finally, studies with the endogenous peptidomimetic 5-aminolevulinic acid have demonstrated relevance to toxicology in the framework of porphyria- and lead-induced neurotoxicity. These studies have consistently demonstrated the dual action of PEPT2 with respect to its apical localization in choroid plexus epithelium and kidney in: 1) effluxing substrates from CSF into choroid plexus, thereby affecting regional pharmacokinetics in brain; and 2) reabsorbing substrates from renal tubular fluid into proximal tubules, thereby affecting systemic pharmacokinetics and exposure. Moreover, these studies have shown that the regional effect of PEPT2 in limiting substrate concentrations in the CSF is more dramatic than its effect in increasing systemic exposure. In the case of 5-aminolevulinic acid, such regional modulation of drug disposition translates directly into significant changes in neurotoxicity.
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