Sawada K, Terada T, Saito H, Hashimoto Y, Inui K I
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Kyoto University, Kyoto, Japan.
J Pharmacol Exp Ther. 1999 Nov;291(2):705-9.
Peptide transporters (PEPT1 and PEPT2) in epithelia play an important role in the absorption of small peptides and peptide-like drugs. Recently, it was demonstrated that various nonpeptidic compounds can be transported by these transporters. In the present study, we focused on the L-amino acid ester compounds and examined the mechanisms of their interaction with rat PEPTs (rPEPTs) using stable transfectants. Valacyclovir, the L-valyl ester prodrug of the antiherpetic agent acyclovir, competitively inhibited [(14)C]glycylsarcosine uptake in the rPEPT1- or rPEPT2-expressing cells. Dixon plot analyses showed that the inhibition constant (K(i)) values of valacyclovir were 2.7 and 0.22 mM for rPEPT1 and rPEPT2, respectively, suggesting that rPEPT2 had higher affinity for this agent. Various L-valine alkyl esters significantly inhibited [(14)C]glycylsarcosine uptake. L-Valine methyl ester (Val-OMe) competitively inhibited [(14)C]glycylsarcosine uptake with K(i) values of 3.6 and 0.83 mM for rPEPT1 and rPEPT2, respectively, indicating that Val-OMe is also a high-affinity substrate for rPEPT2. Val-OMe had a trans-stimulation effect on [(14)C]glycylsarcosine efflux from both transfectants, suggesting the translocation of L-valine methyl ester via rPEPTs. Val-OMe showed the most potent inhibitory effect among the several L-amino acid methyl esters examined. We conclude that Val-OMe, as well as valacyclovir, could be recognized and transported by rPEPT1 and rPEPT2 and that these L-valyl esters showed higher affinity for rPEPT2 as do most substrates of these transporters. Our results suggest that L-valine is a desirable L-amino acid for the esterification of poorly permeable drugs to enhance their oral bioavailability targeting intestinal PEPT1.
上皮细胞中的肽转运体（PEPT1和PEPT2）在小肽和类肽药物的吸收中发挥着重要作用。最近，已证明这些转运体可转运各种非肽类化合物。在本研究中，我们聚焦于L-氨基酸酯化合物，并使用稳定转染细胞研究了它们与大鼠肽转运体（rPEPTs）相互作用的机制。伐昔洛韦是抗疱疹药阿昔洛韦的L-缬氨酰酯前药，竞争性抑制表达rPEPT1或rPEPT2的细胞对[¹⁴C]甘氨酰肌氨酸的摄取。Dixon作图分析表明，伐昔洛韦对rPEPT1和rPEPT2的抑制常数（Kᵢ）值分别为2.7和0.22 mM，这表明rPEPT2对该药物具有更高的亲和力。各种L-缬氨酸烷基酯均显著抑制[¹⁴C]甘氨酰肌氨酸的摄取。L-缬氨酸甲酯（Val-OMe）竞争性抑制[¹⁴C]甘氨酰肌氨酸的摄取，对rPEPT1和rPEPT2的Kᵢ值分别为3.6和0.83 mM，表明Val-OMe也是rPEPT2的高亲和力底物。Val-OMe对两种转染细胞中[¹⁴C]甘氨酰肌氨酸的外排均有反式刺激作用，提示L-缬氨酸甲酯通过rPEPTs进行转运。在所检测的几种L-氨基酸甲酯中，Val-OMe显示出最有效的抑制作用。我们得出结论，Val-OMe与伐昔洛韦一样，可被rPEPT1和rPEPT2识别并转运，并且这些L-缬氨酰酯对rPEPT2显示出更高的亲和力，就像这些转运体的大多数底物一样。我们的结果表明，L-缬氨酸是用于对渗透性差的药物进行酯化以提高其靶向肠道PEPT1的口服生物利用度的理想L-氨基酸。
