INTESTINAL-ABSORPTION OF PEPTIDE DRUGS - ADVANCES IN OUR UNDERSTANDING AND CLINICAL IMPLICATIONS
INTESTINAL-ABSORPTION OF PEPTIDE DRUGS - ADVANCES IN OUR UNDERSTANDING AND CLINICAL IMPLICATIONS
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DOI：
10.1136/gut.35.4.441
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发表时间：
1994-04-01
期刊：
影响因子：
24.5
通讯作者：
HAMMOND, SM
中科院分区：
文献类型：
--
作者：
CATNACH, SM;FAIRCLOUGH, PD;HAMMOND, SM
大多数药物（包括抗生素）的给药途径通常是根据动物研究的生物利用度数据凭经验决定的。然而，对参与人体肠道溶质摄取的转运机制的了解不断增加，提高了我们对肽类药物（包括许多抗生素）吸收的理解。本文将简要讨论二肽在人体内的转运，然后重点介绍肽类药物，特别是f-内酰胺类抗生素的肠道吸收，以及这一领域研究的治疗意义。f-内酰胺化合物是弱酸性肽，因此预计胃肠道吸收较差。然而，这一组中的一些药物具有令人惊讶的良好口服生物利用度，因为利用了刷状缘内小肽的载体介导的转运系统。肽化合物，特别是激素及其类似物，越来越多地用于治疗，但口服生物利用度往往是一个问题。促进肠道吸收的特定药理学设计可能具有巨大益处。药物的设计，特别是利用载体系统是重要的，因为临床上有效的ofa化合物是大大提高，如果它是很好地吸收时，给予mouth.Mammalian肽转运系统要达到血流从肠腔，溶质必须首先通过刷状缘膜的肠细胞微绒毛，穿过肠细胞的细胞质，并退出由基底外侧膜或进入由paracellular路径。蛋白质主要以氨基酸和寡肽的形式从哺乳动物肠道吸收，尽管一些较大的肽也可以完整吸收。这些分子的吸收需要通过细胞旁途径的被动扩散和载体介导的转运。正是这些载体介导的肽转运系统在肽类药物吸收中的应用最近引起了人们的兴趣。30多年前，Newey和Smyth首次报道了哺乳动物肠道中的肽转运。23肽转运在氨基酸的吸收中起主要作用，因此具有营养意义。蛋白酶经腔后和刷状缘消化后，蛋白质被水解为游离氨基酸、二肽和少量三肽的混合物，它们是肠上皮细胞吸收的合适底物。[4]对Hartnup病和胱氨酸尿症患者的研究提供了二肽和氨基酸单独转运的大量证据。在这些条件下，存在遗传缺失，这导致Hartnup病中中性氨基酸和胱氨酸尿症中二元氨基酸的肠道转运缺陷。尽管存在这些转运缺陷，但是，当以二肽的形式呈现给粘膜时，所讨论的氨基酸被正常或接近正常地吸收。此外，在大多数关于二肽转运的研究中，二肽的氨基酸组分的摄取比相应的游离氨基酸的摄取快，表明涉及不同的转运系统。"8完整寡肽的吸收
The route of administration of most drugs, including antibiotics, is often decided empirically based on bioavailability data from animal studies. Increasing knowledge, however, of the transport mechanisms participating in solute uptake from the human intestine has improved our understanding of the absorption of peptide drugs (including a numberof antibiotics). This article will briefly discuss dipeptide transport in humans and then focus on the intestinal absorption of peptide drugs, in particular f-lactam antibiotics, and the therapeutic implications of research in this field. f-lactam compounds are weakly acidic peptides and thus expected to be poorly absorbed from the gastrointestinal tract. Some of the drugs in this group, however, have surprisingly good oral bioavailability because of the utilisation of carrier mediated transport systems for small peptides within the brush border. Peptide compounds, particularly hormones and their analogues, are increasingly used therapeutically, although oral bioavailability is often a problem. Specific pharmacological design to facilitate intestinal absorption is potentially of great benefit. Design of drugs specifically to exploit carrier systems isimportant as the clinical usefulness ofa compound is greatly enhanced if it is well absorbed when given by mouth.Mammalian peptide transport systems To reach the bloodstream from the gut lumen, solutes must either first cross the brush border membrane of the entero-cyte microvilli, traverse the enterocyte cytoplasm, and exit by the basolateral membrane or enter by the paracellular route. Protein is predominantly absorbed from the mammalian gut as amino acids and oligopeptides, although some larger peptides may also be absorbed intact.'Absorptionof these molecules entails both passive diffusion through the para-cellular pathways, and facilitated by carrier mediated trans-port. It is the use of these carrier mediated peptide transport systems in the absorption of peptide drugs that has recently provoked interest. Peptide transport in mammalian gut was first reported by Newey and Smyth more than 30 years ago. 23 Peptide transport plays a major part in the absorption of amino acids and is therefore of nutritional significance. Afterluminal and brush border digestion by proteases, proteins are hydrolysed to a mixture of free aminoacids, dipeptides, and a few tripeptides, which are suitable substrates for absorption into the enterocyte. 4 Much of the evidence for separate dipeptide and amino acid transport has been provided by studies in patients with Hartnup disease and cystinuria. In these conditions there is a genetic deletion, which results in an intestinal transport defect for neutral amino acids in Hartnup disease'and dibasic amino acids in cystinuria.'Despite these transport defects, however, the amino acids in question are absorbed normally or near normally when presented to the mucosa in the form of dipeptides. Furthermore, in most studies on dipeptide transport, uptake of the amino acid components ofdipeptides is faster thanthat of the corres-ponding free amino acids, showing that different transport systems are involved." 8 Absorption of intact oligopeptides