Evaluation of a Thiodipeptide, L-Phenylalanyl-Ψ[CS-N]-L-alanine, as a Novel Probe for Peptide Transporter 1
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- ARAKAWA Hiroshi
- Faculty of Pharmacy, Takasaki University of Health and Welfare
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- SAITO Sachi
- Faculty of Pharmacy, Takasaki University of Health and Welfare
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- KANAGAWA Masahiko
- Faculty of Pharmacy, Takasaki University of Health and Welfare
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- KAMIOKA Hiroki
- Faculty of Pharmacy, Takasaki University of Health and Welfare
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- YANO Kentaro
- Faculty of Pharmacy, Takasaki University of Health and Welfare
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- MORIMOTO Kaori
- Department of Drug Absorption and Pharmacokinetics, Tohoku Pharmaceutical University
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- OGIHARA Takuo
- Faculty of Pharmacy, Takasaki University of Health and Welfare
書誌事項
- 公開日
- 2014
- 資源種別
- journal article
- DOI
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- 10.2133/dmpk.dmpk-14-rg-047
- 公開者
- 日本薬物動態学会
この論文をさがす
説明
l-Phenylalanyl-Ψ[CS-N]-l-alanine (Phe-Ψ-Ala), a thiourea dipeptide, was evaluated as a probe for peptide transporter 1 (PEPT1). Uptake of Phe-Ψ-Ala in PEPT1-overexpressing HeLa cells was significantly higher than that in vector-transfected HeLa cells and the Km value was 275 ± 32 µM. The uptake was pH-dependent, being highest at pH 6.0, and was significantly decreased in the presence of PEPT1 inhibitors [glycylsarcosine (Gly-Sar), cephalexin, valaciclovir, glycylglycine, and glycylproline]. In metabolism assay using rat intestinal mucosa, rat hepatic microsomes, and human hepatocytes, the amount of Phe-Ψ-Ala was unchanged, whereas phenylalanylalanine was extensively decomposed. The clearance, distribution volume, and half-life of intravenously administered Phe-Ψ-Ala in rats were 0.151 ± 0.008 L/h/kg, 0.235 ± 0.012 L/kg, and 1.14 ± 0.07 h, respectively. The maximum plasma concentration of orally administered Phe-Ψ-Ala (2.31 ± 0.60 µg/mL) in the presence of Gly-Sar was significantly decreased compared with that in the absence of glycylsarcosine (3.74 ± 0.44 µg/mL), suggesting that the intestinal absorption of Phe-Ψ-Ala is mediated by intestinal PEPT1. In conclusion, our results indicate that Phe-Ψ-Ala is a high-affinity, metabolically stable, non-radioactive probe for PEPT1, and it should prove useful in studies of PEPT1, e.g., for predicting drug-drug interactions mediated by PEPT1 in vitro and in vivo.
収録刊行物
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- Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ
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Ｄｒｕｇ Ｍｅｔａｂｏｌｉｓｍ ａｎｄ Ｐｈａｒｍａｃｏｋｉｎｅｔｉｃｓ 29 (6), 470-474, 2014
日本薬物動態学会
