相信你的直觉：肠道限制药物的策略与技巧。
Trust Your Gut: Strategies and Tactics for Intestinally Restricted Drugs.
作者信息
Dorel Ruth, Wong Alice R, Crawford James J
机构信息
Genentech, Inc., South San Francisco, California 94080, United States.
出版信息
ACS Med Chem Lett. 2023 Feb 22;14(3):233-243. doi: 10.1021/acsmedchemlett.3c00001. eCollection 2023 Mar 9.
Abstract
Non-absorbable small-molecule drugs targeted to the gut represent an alternative approach to safe, non-systemic therapeutics. Such drugs remain confined to the gastrointestinal tract upon oral dosing by virtue of their limited passive permeability, increasing the local concentration at the site of action while minimizing exposure elsewhere in the body. Herein we review the latest advances in the field of gut-restricted therapeutics, highlighting the different strategies and tactics that medicinal chemists have employed in pursuit of drugs with minimal intestinal absorption.
摘要
靶向肠道的不可吸收小分子药物是一种实现安全、非全身性治疗的替代方法。这类药物口服给药后，由于其被动通透性有限，会局限于胃肠道内，从而提高作用部位的局部浓度，同时将身体其他部位的暴露降至最低。在此，我们综述肠道限制疗法领域的最新进展，重点介绍药物化学家为研发肠道吸收最少的药物所采用的不同策略和方法。
相似文献
1
Trust Your Gut: Strategies and Tactics for Intestinally Restricted Drugs.相信你的直觉：肠道限制药物的策略与技巧。
ACS Med Chem Lett. 2023 Feb 22;14(3):233-243. doi: 10.1021/acsmedchemlett.3c00001. eCollection 2023 Mar 9.
2
Intestinal targeting of drugs: rational design approaches and challenges.药物的肠道靶向：合理设计方法与挑战。
Curr Top Med Chem. 2013;13(7):776-802. doi: 10.2174/1568026611313070002.
3
Interplay of metabolism and transport in determining oral drug absorption and gut wall metabolism: a simulation assessment using the "Advanced Dissolution, Absorption, Metabolism (ADAM)" model.代谢与转运在决定口服药物吸收和肠道壁代谢中的相互作用：应用“先进的溶解、吸收、代谢（ADAM）”模型进行的模拟评估。
Curr Drug Metab. 2010 Nov;11(9):716-29. doi: 10.2174/138920010794328913.
4
Enhanced gastrointestinal passive paracellular permeability contributes to the obesity-associated hyperoxaluria.增强的胃肠道被动细胞旁通透性导致肥胖相关的高草酸尿症。
Am J Physiol Gastrointest Liver Physiol. 2019 Jan 1;316(1):G1-G14. doi: 10.1152/ajpgi.00266.2018. Epub 2018 Oct 11.
5
Non-systemic drugs: a critical review.非系统性药物：批判性评价。
Curr Pharm Des. 2012;18(10):1434-45. doi: 10.2174/138161212799504858.
6
Screening for effective cell-penetrating peptides with minimal impact on epithelial cells and gut commensals .筛选对上皮细胞和肠道共生菌影响最小的有效细胞穿透肽。
Front Pharmacol. 2022 Nov 2;13:1049324. doi: 10.3389/fphar.2022.1049324. eCollection 2022.
7
Drug absorption in gastrointestinal disease with particular reference to malabsorption syndromes.胃肠道疾病中的药物吸收，特别涉及吸收不良综合征。
Clin Pharmacokinet. 1977 Jan-Feb;2(1):45-60. doi: 10.2165/00003088-197702010-00004.
8
Site of drug absorption after oral administration: assessment of membrane permeability and luminal concentration of drugs in each segment of gastrointestinal tract.口服给药后药物的吸收部位：胃肠道各段药物膜通透性和管腔浓度的评估
Eur J Pharm Sci. 2006 Nov;29(3-4):240-50. doi: 10.1016/j.ejps.2006.06.004. Epub 2006 Jun 27.
9
Oral administration of non-absorbable delayed release 6-mercaptopurine is locally active in the gut, exerts a systemic immune effect and alleviates Crohn's disease with low rate of side effects: results of double blind Phase II clinical trial.口服不可吸收的缓释6-巯基嘌呤在肠道局部具有活性，发挥全身免疫效应并以低副作用发生率缓解克罗恩病：II期双盲临床试验结果
Clin Exp Immunol. 2015 Aug;181(2):362-72. doi: 10.1111/cei.12640.
10
Using Physiologically Based Pharmacokinetic (PBPK) Modeling to Evaluate the Impact of Pharmaceutical Excipients on Oral Drug Absorption: Sensitivity Analyses.使用基于生理学的药代动力学（PBPK）模型评估药用辅料对口服药物吸收的影响：敏感性分析
AAPS J. 2016 Nov;18(6):1500-1511. doi: 10.1208/s12248-016-9964-4. Epub 2016 Aug 12.
引用本文的文献
1
lysyl-tRNA synthetase inhibitors define the interplay between solubility and permeability required to achieve efficacy.赖氨酸 tRNA 合成酶抑制剂定义了实现疗效所需的溶解度和渗透性之间的相互作用。
Sci Transl Med. 2024 Oct 23;16(770):eadm8631. doi: 10.1126/scitranslmed.adm8631.
2
Cryptosporidium PI(4)K inhibitor EDI048 is a gut-restricted parasiticidal agent to treat paediatric enteric cryptosporidiosis.隐孢子虫 PI(4)K 抑制剂 EDI048 是一种局限于肠道的杀寄生虫药物，可用于治疗儿科肠道隐孢子虫病。
Nat Microbiol. 2024 Nov;9(11):2817-2835. doi: 10.1038/s41564-024-01810-x. Epub 2024 Oct 8.
3
Tailoring FXR Modulators for Intestinal Specificity: Recent Progress and Insights.靶向 FXR 调节剂以实现肠道特异性：最新进展和研究进展。
Molecules. 2024 Apr 27;29(9):2022. doi: 10.3390/molecules29092022.
本文引用的文献
1
Discovery of Tenapanor: A First-in-Class Minimally Systemic Inhibitor of Intestinal Na/H Exchanger Isoform 3.替那帕诺的发现：一种首创的肠道钠/氢交换蛋白3亚型的低全身暴露抑制剂
ACS Med Chem Lett. 2022 Apr 11;13(7):1043-1051. doi: 10.1021/acsmedchemlett.2c00037. eCollection 2022 Jul 14.
2
Discovery of ()-3-(3-((2-Cyano-4'-dimethylaminobiphenyl-4-ylmethyl)cyclohexanecarbonylamino)-5-fluorophenyl)acrylic Acid Methyl Ester, an Intestine-Specific, FXR Partial Agonist for the Treatment of Nonalcoholic Steatohepatitis.发现（）-3-（3-（（2-氰基-4'-二甲基氨基联苯-4-基甲基）环己烷甲酰氨基）-5-氟苯基）丙烯酸甲酯，一种用于治疗非酒精性脂肪性肝炎的肠道特异性、FXR 部分激动剂。
J Med Chem. 2022 Jul 28;65(14):9974-10000. doi: 10.1021/acs.jmedchem.2c00641. Epub 2022 Jul 7.
3
Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease.ZED1227的特点：首个用于乳糜泻治疗且正在进行临床评估的组织转谷氨酰胺酶抑制剂。
Cells. 2022 May 17;11(10):1667. doi: 10.3390/cells11101667.
4
Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists.肠道受限 LXR 反向激动剂的抗高血脂活性。
ACS Chem Biol. 2022 May 20;17(5):1143-1154. doi: 10.1021/acschembio.2c00057. Epub 2022 Apr 13.
5
Safety, pharmacokinetic, and pharmacodynamic study of sibofimloc, a novel FimH blocker in patients with active Crohn's disease.新型FimH阻断剂西博菲姆洛克在活动性克罗恩病患者中的安全性、药代动力学和药效学研究。
J Gastroenterol Hepatol. 2022 May;37(5):832-840. doi: 10.1111/jgh.15828. Epub 2022 Mar 18.
6
Discovery of Gut-Restricted Small-Molecule Inhibitors of Intestinal Sodium-Dependent Phosphate Transport Protein 2b (NaPi2b) for the Treatment of Hyperphosphatemia.发现肠道受限的小分子抑制剂肠道钠依赖性磷酸转运蛋白 2b（NaPi2b）用于治疗高磷血症。
J Med Chem. 2022 Feb 10;65(3):1946-1960. doi: 10.1021/acs.jmedchem.1c01474. Epub 2022 Jan 17.
7
Maralixibat: First Approval.马拉利昔巴特：首次批准。
Drugs. 2022 Jan;82(1):71-76. doi: 10.1007/s40265-021-01649-0.
8
Odevixibat: First Approval.奥贝胆酸：首次获批。
Drugs. 2021 Oct;81(15):1781-1786. doi: 10.1007/s40265-021-01594-y.
9
Gut-Restricted Selective Cyclooxygenase-2 (COX-2) Inhibitors for Chemoprevention of Colorectal Cancer.用于结直肠癌化学预防的肠道限制型选择性环氧化酶-2（COX-2）抑制剂。
J Med Chem. 2021 Aug 12;64(15):11570-11596. doi: 10.1021/acs.jmedchem.1c00890. Epub 2021 Jul 19.
10
Oral Delivery of Biologics in Inflammatory Bowel Disease Treatment.炎症性肠病治疗中生物制剂的口服给药
Front Bioeng Biotechnol. 2021 Jun 3;9:675194. doi: 10.3389/fbioe.2021.675194. eCollection 2021.
Zotero 插件