de Korwin Jean-Dominique, Ducrotté Philippe, Vallot Thierry
Service de médecine interne H, Hôpital Central, CHU de Nancy.
Presse Med. 2004 Jun 19;33(11):746-54. doi: 10.1016/s0755-4982(04)98731-3.
The proton pump inhibitors (PPIs) are now universally considered the treatment of choice for management of gastric-acid-related diseases, mainly gastro-oesophageal reflux disease (GERD). These drugs share similar properties: general structure, acid-activation step, covalent binding to the proton pump of the gastric parietal cell via the production of covalent disulphide bonds, relatively stable inhibition of H+,K+-ATPase. However, the older PPIs (omeprazole, lansoprazole et pantoprazole) have notable limitations. These drugs exhibit substantial interpatient variability and may have significant interactions with other drugs. These first-generation PPIs also do not achieve a rapid and sustained suppression of gastric acid, leading to the development of new acid-pump antagonists. The new-generation PPIs, esomeprazole and rabeprazole, offer several pharmacokinetic advantages: lower oxidative hepatic metabolism rate via the CYP 2C19 reducing the activity variations due to genetic polymorphisms and decreasing the risk of significant drug-drug interactions (advantages mainly for rabeprazole), lower metabolic clearance of esomeprazole (S-enantiomer of omeprazole) increasing plasma concentrations and acid suppression of this new PPI, higher accumulation of rabeprazole in the parietal cell due to its higher pKa. Gastric pH studies and therapeutic trials have demonstrated significant advantages of esomeprazole and rabeprazole compared with the older PPIs, which omeprazole is the prototype: a greater inhibition of acid secretion, a more rapid onset of action to provide reflux symptoms relief over 24 hours with lower GERD-related cost for rabeprazole, a sustained acid suppression, cost-effectiveness advantages for esomeprazole in the healing and maintenance of erosive esophagitis compared with lansoprazole, reduced potential for clinically significant drug-drug interactions with rabeprazole compared with omeprazole and esomeprazole. Due to their properties, esomeprazole and rabeprazole are the best candidates for "on demand" treatment of GERD.
质子泵抑制剂（PPIs）如今被普遍认为是治疗胃酸相关疾病（主要是胃食管反流病，即GERD）的首选药物。这些药物具有相似的特性：一般结构、酸激活步骤、通过形成共价二硫键与胃壁细胞的质子泵共价结合、对H⁺，K⁺-ATP酶的相对稳定抑制。然而，老一代PPIs（奥美拉唑、兰索拉唑和泮托拉唑）存在显著局限性。这些药物在患者之间表现出很大的变异性，并且可能与其他药物发生显著相互作用。这些第一代PPIs也无法实现对胃酸的快速持续抑制，从而促使了新型酸泵拮抗剂的研发。新一代PPIs，即埃索美拉唑和雷贝拉唑，具有若干药代动力学优势：通过CYP 2C19的肝脏氧化代谢率较低，减少了因基因多态性导致的活性差异，并降低了发生显著药物相互作用的风险（主要是雷贝拉唑的优势）；埃索美拉唑（奥美拉唑的S-对映体）的代谢清除率较低，提高了血浆浓度以及这种新型PPI的抑酸作用；雷贝拉唑因其较高的pKa在壁细胞中的蓄积量更高。胃pH值研究和治疗试验已证明，与以奥美拉唑为原型的老一代PPIs相比，埃索美拉唑和雷贝拉唑具有显著优势：对胃酸分泌的抑制作用更强，起效更快，能在24小时内缓解反流症状，雷贝拉唑的GERD相关成本更低；能持续抑制胃酸，与兰索拉唑相比，埃索美拉唑在糜烂性食管炎的愈合和维持治疗方面具有成本效益优势；与奥美拉唑和埃索美拉唑相比，雷贝拉唑发生具有临床意义的药物相互作用的可能性降低。鉴于其特性，埃索美拉唑和雷贝拉唑是GERD“按需”治疗的最佳选择。
