Susceptibility of the H2-receptor antagonists cimetidine, famotidine and nizatidine, to metabolism by the gastrointestinal microflora
Susceptibility of the H2-receptor antagonists cimetidine, famotidine and nizatidine, to metabolism by the gastrointestinal microflora
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DOI：
10.1016/s0378-5173(02)00018-2
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发表时间：
2002-04-26
影响因子：
5.8
通讯作者：
Lacey, LF
中科院分区：
文献类型：
--
作者：
Basit, AW;Newton, JM;Lacey, LF
H-2受体拮抗剂雷尼替丁以前已被证明是结肠细菌代谢的底物。本研究的目的是评估其他H-2受体拮抗剂，西咪替丁，法莫替丁和尼扎替丁，结肠细菌的体外稳定性。将100 mg每种药物引入由接种新鲜排出的人粪便（10% w/v）的缓冲培养基组成的单独分批培养发酵罐（100 ml）中。对照实验，在不存在粪便的缓冲介质中使用等效药物量。也是并行运行的。在24小时内以设定的时间间隔取出样品，随后通过HPLC进行分析。还通过UV光谱法和质谱法对从发酵罐中取出的样品的选择进行分析。在发酵系统中的初始溶解阶段之后，注意到尼扎替丁浓度随时间显著下降，12小时后几乎没有药物残留，从而表明药物被结肠细菌降解和代谢。西咪替丁或法莫替丁或对照缓冲液系统中的任何药物均未观察到此类浓度下降。尼扎替丁的代谢反应途径是复杂的，尽管UV和质谱分析表明代谢是通过分子内N-氧化物键的裂解启动的。这些结果与从先前的研究中获得的结果相结合表明，在四种市售的H-2受体拮抗剂中，尼扎替丁和雷尼替丁容易被结肠细菌代谢，这反过来又对药物递送和吸收产生影响。(C)2002爱思唯尔科技有限公司。保留所有权利。
The H-2-receptor antagonist ranitidine has previously been shown to be a substrate for colonic bacterial metabolism. The objective of the present study was to assess the in vitro stability of the other H-2-receptor antagonists, cimetidine, famotidine and nizatidine, to colonic bacteria. One hundred milligrams of each drug were introduced into individual batch culture fermenters (100 ml) consisting of buffer medium inoculated with freshly voided human faeces (10% w/v). Control experiments, equivalent drug quantities in buffer medium without the presence of faeces. were also run in parallel. Samples were removed at set time intervals over a 24 h period and were subsequently analysed by HPLC. A selection of the samples removed from the fermenters was also subjected to analysis by UV spectroscopy and mass spectrometry. Following an initial dissolution phase in the fermentation system, a marked decline in nizatidine concentration was noted over time with virtually no drug remaining after 12 h, thereby suggesting degradation and metabolism of the drug by colonic bacteria. No such decline in concentration was noted for cimetidine or famotidine or for any of the drugs in the control buffer systems. The metabolic reaction pathway for nizatidine was complex, although UV and mass spectrometry analysis indicated that metabolism was initiated via cleavage of an N-oxide bond within the molecule. These results in combination with those obtained from a previous study indicate that of the four commercially available H-2-receptor antagonists, nizatidine and ranitidine are susceptible to metabolism by colonic bacteria, which in turn has ramifications for drug delivery and absorption. (C) 2002 Elsevier Science B.V. All rights reserved.