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Enterohepatic Circulation

儿科

关键词儿科 临床研究术语 肝胆疾病

词汇介绍

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解析

enterohepatic

释    义   adj. 肠肝的

例    句   Hypercholic acidemia is caused by the interruption of enterohepatic circulation and deterioration of hepatic function after portasystemic shunt. 高胆酸血症主要为门体分流术后肝肠循环阻断和肝功能恶化所致。

 

circulation  英/sɜːkjʊ'leɪʃ(ə)n/  美/,sɝkjə'leʃən/

释    义   n. 流通,传播;循环;发行量;(图书的)借出

例    句   Hemoglobin was the carrier of oxygen in blood circulation. 血红蛋白是血液循环中输送氧的载体。

概述

胆汁酸的肠肝循环是一个非常严格的调控过程,机体利用胆汁流和胆汁池大小,通过一系列的网状调控机制使胆汁酸的合成、摄取、排泄以及重吸收过程处于动态平衡,以维持机体稳态。而在病理状态下,这种调控机制出现障碍,胆汁流量减少,循环系统及细胞内胆汁蓄积造成细胞损伤。胆汁酸的肝肠循环在肠道中,结合型胆汁酸在回肠末端和结肠上段肠道细菌的作用下解离成游离型胆汁酸,随之被细菌7a-脱氢酶转化为次级胆汁酸:脱氧胆酸和石胆酸, 二者在结肠通过弥散作用重吸收或通过粪便排出体外。因此,在回肠末端结合型胆汁酸和游离型胆汁

Oral Coadministration of β-Glucuronidase to Increase Exposure of Extensively Glucuronidated Drugs That Undergo Enterohepatic Recirculation复制标题

口服 β-葡萄糖醛酸苷酶联合给药增加经肠肝再循环的广泛葡萄糖醛酸化药物的暴露

发表时间:2012-02-21

影响因子:3.1

作者: Gary Eichenbaum

期刊:J Pharm Sci

Strategies for increasing the bioavailability of compounds that undergo extensive first-pass metabolism have generally fallen into two categories: chemical and drug delivery based. Chemical-based approaches include structural modification of the parent compound, coadministration of an enzyme inhibitor, inhibition of efflux transporters such as p-glycoprotein, or coadministration of a buffering agent such as sodium bicarbonate. Structural modification is a common approach used prior to candidate selection and in the development of backup compounds. For example, nitrofenac, a structural analog of diclofenac, does not produce the intestinal toxicities (e.g., ulcerations) that are observed with diclofenac.An example of coadministration of an inhibitor is methoxaslen, which is a CYP2A6 inhibitor that blocks the metabolism of nicotine and has been shown to decrease nicotine clearance, increase nicotine bioavail- ability, and decrease smoking behaviors.Inhibitors such as ketoconazole have been used to reduce the extent of metabolism of cytotoxic and antiviral drugs, thereby improving the bioavailability and efficacy of these agents.Drug delivery approaches include bypassing duodenal or gastric metabolism and delivering a compound to the colon through the use of a controlled-release delivery system or bypassing the first pass to liver through transdermal, oral cavity, or parenteral routes.Although both chemical- and drug delivery-based approaches can be effective for overcoming extensive first-pass metabolism, they can also have limitations. For example, structural modification of acompound that is in clinical trials generates a com- pletely new chemical entity that requires a new development program, including nonclinical toxicology, resulting in increased time, cost, and risk. Furthermore, chemical modification may not be feasible in cases wherein the site of metabolism is essential for the biological activity of the chemical series. In cases wherein multiple enzymes form a toxic metabolite, the use of enzyme inhibitors may be of limited value. If there are no regional differences in gut metabolism or there is poor colonic absorption, it is unlikely that an oral controlled-release delivery approach would deliver adequate drug levels.

译文

提高经过广泛的首次代谢的化合物的生物利用度的策略通常分为两类:基于化学和药物传递的。基于化学的方法包括母体化合物的结构修饰、酶抑制剂的共给药、对p-糖蛋白等外排转运体的抑制或缓冲剂(如碳酸氢钠)的共给药。结构修饰是一种常用的方法,用于候选化合物的筛选和后备化合物的开发。例如,硝基芬酸是双氯芬酸的结构类似物,它不会产生双氯芬酸所观察到的肠道毒性(如溃疡)。联合使用抑制剂的一个例子是甲氧西林,它是一种cyp2a6抑制剂,可以阻断尼古丁的代谢,并已被证明会降低尼古丁的清除率,增加尼古丁的生物利用度,减少吸烟行为。酮康唑等抑制剂已被用于降低细胞毒性药物和抗病毒药物的代谢程度,从而提高这些药物的生物利用度和疗效。药物传递途径包括绕过十二指肠或胃的代谢,通过控制释放传递系统将化合物传递到结肠,或通过经皮、口腔或肠外途径绕过第一次传递到肝脏。尽管基于化学和药物传递的方法都可以有效地克服广泛的首次通过代谢,但它们也有局限性。例如,在临床试验中对复合物进行结构改造,产生一种全新的化学实体,需要新的开发计划,包括非临床毒理学,从而增加时间、成本和风险。此外,在代谢部位对化学系列的生物活性至关重要的情况下,化学修饰可能不可行。在多种酶形成有毒代谢物的情况下,使用酶抑制剂的价值可能有限。如果肠道代谢没有区域性差异或结肠吸收不良,口服控释给药方法不太可能提供足够的药物水平。