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首页> 外文学位 >Intestinal absorption of low permeability drugs: A transporter- and enzyme-targeted approach.
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Intestinal absorption of low permeability drugs: A transporter- and enzyme-targeted approach.

机译：低渗透性药物的肠道吸收：一种针对转运蛋白和酶的方法。

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摘要

This dissertation is the investigation of a prodrug strategy for increased oral absorption via transport by hPEPTI and activation by hVACVase. L-Valine, L-isoleucine and L-phenylalanine esters of a guanidino-containing model compound [3-(hydroxymethyl)phenyl]guanidine (3-HPG) were synthesized and evaluated for the feasibility of this prodrug approach to guanidino-containing drugs. In HeLa/hPEPTI cells, Val-3-HPG and Ile-3-HPG exhibited high affinity to hPEPTI (IC50: 0.65 mM and 0.63 mM, respectively), and all three L-amino acid esters showed higher uptake (2.6- to 9-fold) than the parent compound 3-HPG. Val-3-HPG and Ile-3-HPG demonstrated remarkable Caco-2 permeability enhancement, and Val-3-1-1PG exhibited comparable permeability to valacyclovir. The low permeability of D-Val-3-HPG and the inhibition studies indicated that hPEPTI was the predominant transporter responsible for Val-3HPG permeability. In rat perfusion studies, Val-3-HPG and Ile-3-HPG permeabilities were significantly higher than 3-HPG, and exceeded/matched the high-permeability standard metoprolol, respectively. In HeLa and Caco-2 cell homogenates, the hydrolysis of amino acid esters was faster than in the corresponding buffer, indicating predominant enzymatic activation. All the L-amino acid 3-HPG esters were found to be good substrates of hVACVase, and exhibited higher specificity constants than that for valacyclovir (kcat/Km in mM-1·s-1, Val-3-HPG, 3370; Ile-3-HPG, 1580; Phe-3-HPG, 1660; valacyclovir, 850), presumably resulting from high binding affinity to hVACVase as well as favorable leaving group lability. The results in this study suggested that the leaving group had an effect on both binding and specific activity of hVACVase-catalyzed prodrug activation. hVACVase is an ideal target for alpha-amino acid ester prodrugs with relatively labile leaving groups but is unable to activate amide prodrugs.
机译：本论文研究了通过hPEPTI转运和hVACVase活化增加口服吸收的前药策略。合成了含胍基模型化合物[3-（羟甲基）苯基]胍（3-HPG）的L-缬氨酸，L-异亮氨酸和L-苯丙氨酸酯，并评估了该前药方法对含胍基药物的可行性。在HeLa / hPEPTI细胞中，Val-3-HPG和Ile-3-HPG对hPEPTI表现出高亲和力（IC50分别为0.65 mM和0.63 mM），并且所有三种L-氨基酸酯均显示较高的摄取（2.6至9） -倍）比母体化合物3-HPG。 Val-3-HPG和Ile-3-HPG表现出显着的Caco-2渗透性增强，Val-3-1-1PG表现出与伐昔洛韦相当的渗透性。 D-Val-3-HPG的低渗透性和抑制研究表明，hPEPTI是负责Val-3HPG渗透性的主要转运蛋白。在大鼠灌注研究中，Val-3-HPG和Ile-3-HPG的通透性显着高于3-HPG，并分别超过/匹配了高通透性标准美托洛尔。在HeLa和Caco-2细胞匀浆中，氨基酸酯的水解比在相应的缓冲液中快，表明主要是酶促活化。发现所有L-氨基酸3-HPG酯均是hVACVase的良好底物，并且表现出比伐昔洛韦更高的特异性（kcat / Km，mM-1·s-1，Val-3-HPG，3370； Ile -3-HPG，1580； Phe-3-HPG，1660；伐昔洛韦，850），大概是由于对hVACVase的高结合亲和力和良好的离去基团不稳定性所致。这项研究的结果表明，离去基团对hVACVase催化的前药活化的结合和比活性都有影响。 hVACVase是具有相对不稳定的离去基团的α-氨基酸酯前药的理想靶标，但无法激活酰胺前药。

著录项

  • 作者

    Sun, Jing.;

  • 作者单位

    University of Michigan.;

  • 授予单位 University of Michigan.;
  • 学科 Chemistry Pharmaceutical.;Health Sciences Pharmacy.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 95 p.
  • 总页数 95
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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