Huber R, Kohl B, Sachs G, Senn-Bilfinger J, Simon W A, Sturm E
Research Laboratories Byk Gulden, Konstanz, Germany.
Aliment Pharmacol Ther. 1995 Aug;9(4):363-78. doi: 10.1111/j.1365-2036.1995.tb00394.x.
Inhibition of the gastric proton pump is gaining acceptance as the treatment of choice for severe gastrooesophageal reflux disease, and for treatment of duodenal and gastric ulceration. Three of these drugs are now available (omeprazole, lansoprazole and pantoprazole) and more are being developed. Proton pump inhibitors share the same core structure, but differ in terms of substituents on this core. The substitutions are able to modify some important chemical properties of the compounds. For example, pantoprazole is significantly more acid-stable than omeprazole or lansoprazole. E3810 is significantly less stable than the other compounds. We present an explantation for this finding that depends on the relative pK values for the pyridine and benzimidazole nitrogens, especially the former. Pantoprazole formulated in an enteric-coated tablet displays high bioavailability and linear pharmacokinetics whether on single or multiple dose regimens. Although all three proton pump inhibitors provide a similar chemical conversion to sulphenamides, which are highly reactive cysteine reagents, these reagents derivatize different cysteines in the extracytoplasmic or membrane domain of the pump and inhibit the pump at different rates. Whereas the differences in chemical reactivity can be explained by the solution chemistry of the compounds, selective derivatization of different cysteines on the protein argues for an involvement of pump structure in response to the presence of the proton pump inhibitor on its luminal surface. This suggests that the proton pump inhibitors, which were originally designed to take advantage of only the highly acidic space generated in the parietal cell by the production of the sulphenamide, are made even more selective by the protein they target. Pantoprazole is metabolized by a combination of phase I and phase II metabolism, and has also been shown to have a very low potential for drug interaction. Studies of acid secretion in man have shown this compound to be an effective and long lasting inhibitor of acid secretion. The pharmacodynamics explain the cumulative effect of repeated doses and maximal acid secretory capacity with a once daily dosage.
抑制胃质子泵作为重症胃食管反流病以及十二指肠和胃溃疡的首选治疗方法正逐渐被认可。目前已有三种此类药物（奥美拉唑、兰索拉唑和泮托拉唑）上市，且更多药物正在研发中。质子泵抑制剂具有相同的核心结构，但该核心上的取代基有所不同。这些取代基能够改变化合物的一些重要化学性质。例如，泮托拉唑比奥美拉唑或兰索拉唑在酸性环境下更稳定。E3810比其他化合物稳定性明显更低。我们对这一发现给出了一种解释，该解释取决于吡啶和苯并咪唑氮的相对pK值，尤其是前者。肠溶包衣片剂型的泮托拉唑无论是单剂量还是多剂量给药方案，均显示出高生物利用度和线性药代动力学。尽管所有三种质子泵抑制剂都能发生类似的化学转化生成具有高反应活性的半磺酰胺，这些半磺酰胺是与半胱氨酸反应的试剂，但这些试剂会使泵的胞外或膜结构域中的不同半胱氨酸发生衍生化，并以不同速率抑制泵。虽然化合物的溶液化学性质可以解释其化学反应性的差异，但蛋白质上不同半胱氨酸的选择性衍生化表明，泵的结构参与了对其腔表面质子泵抑制剂存在的反应。这表明，质子泵抑制剂最初设计时仅利用壁细胞中由半磺酰胺产生的高酸性空间，而它们所作用的蛋白质使其具有了更高的选择性。泮托拉唑通过I相和II相代谢的联合作用进行代谢，并且还显示出药物相互作用的可能性非常低。人体胃酸分泌研究表明，该化合物是一种有效且持久的胃酸分泌抑制剂。药效学解释了重复给药的累积效应以及每日一次给药剂量下的最大胃酸分泌能力。
