Vonoprazan: MarKed Competition for PPIs?
Vonoprazan: MarKed Competition for PPIs?
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Vonoprazan：质子泵抑制剂的竞争激烈？
DOI：
10.1007/s10620-016-4164-8
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发表时间：
2016
影响因子：
3.1
通讯作者：
Sachs,George
中科院分区：
文献类型：
--
作者：
Scott,DavidR;Marcus,ElizabethA;Sachs,George
用于治疗酸相关疾病（例如胃食管反流病（GERD）和消化性溃疡病（PUD））以及幽门螺杆菌感染的当代疗法分别依赖于酸抑制来缓解症状、愈合和根除。自30年前奥美拉唑获批用于临床以来，质子泵抑制剂对胃酸分泌途径的最后一步胃H+，K+-ATP酶的抑制一直是治疗的选择[1]。PPI在缓解GERD和PUD症状和治愈方面比H2受体拮抗剂（H2 RA）和抗酸剂有很大改善。PPI是弱碱，蓄积在胃壁细胞的酸性（pH* 1）分泌小管中。作为前药，它们需要质子化以实现其活性形式。一旦质子化，它们迅速且不可逆地结合并抑制小管膜中主动分泌的质子泵。由于并非所有质子泵在任何一个时间点都有活性，并且PPI在单次给药后不存在有效浓度，因此需要多次给药才能抑制新的活性泵并实现酸分泌的稳态抑制。为了用单次PPI剂量抑制尽可能多的泵，药物必须在餐前约30分钟给药，以确保由于餐后胃泌素释放的影响，小管膜上存在最大数量的泵。此外，由于H+，K+-ATP酶的t1/2为 * 50 h，因此重新合成的泵占每日活性泵的 * 25%[2]。由于PPI的血浆t1/2较短（60-90 min），因此PPI每日一次或两次给药均不会抑制夜间合成泵。总之，这些过程有助于酸抑制的缓慢起效，第一次给药时泵的抑制率为 * 40%，每天一次或每天两次给药3天后稳态时泵的抑制率为 * 70或80%[3]。PPI在肝脏中通过细胞色素CYP 2C 19代谢[4]，其多态性影响药物的药代动力学和药效学。CYP 2C 19多态性的表型为快速代谢型（RM）、中间代谢型（IM）和慢代谢型（PM）[5]。单剂量奥美拉唑的血浆“驻留时间”与PM [IM][RM]不同等位基因之间的代谢速率直接相关，这反过来又影响酸抑制水平，再次影响PM [IM][RM]。代谢率影响GERD患者粘膜破损的愈合率，RM的治愈率最低，PM的治愈率最高（RM\IM\PM）。代谢速率的差异也影响H的功效。幽门螺杆菌根除，因为根除率与酸抑制程度密切相关。尽管PPI在酸抑制方面上级H2 RA，但仍需要更有效、更快起效的酸抑制剂，以更好地缓解症状和促进粘膜愈合。二氢吡啶类钙通道阻滞剂（CCBs）抑制胃H+，K+-ATP酶的另一种机制，
Contemporary therapies for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD) and peptic ulcer disease (PUD), as well as Helicobacter pylori infection, rely on acid suppression for symptom relief, healing, and eradication, respectively. Inhibition of the gastric H+, K+-ATPase, the final step in the acid secretion pathway, by proton pump inhibitors has been the treatment of choice since the approval of omeprazole for clinical use 30 years ago [1]. PPIs were a vast improvement over the H2 receptor antagonists (H2RAs) and antacids for symptom relief and for healing of GERD and PUD. PPIs are weak bases that accumulate in the acidic (pH* 1) secretory canaliculus of the gastric parietal cells. Being prodrugs, they require protonation to achieve their active form. Once protonated, they rapidly and irreversibly bind to and inhibit actively secreting proton pumps in the canalicular membrane. Because not all proton pumps are active at any one time and PPIs are not present at effective concentrations after a single administration, several doses are required to inhibit newly active pumps and to achieve steady-state inhibition of acid secretion. To inhibit as many pumps as possible with a single PPI dose, the drug must be administered about 30 min before a meal to ensure the maximal number of pumps is present at the canalicular membrane, due to the effects of post-prandial gastrin release. Furthermore, since the t1/2 of the H+, K+-ATPase is* 50 h, de novo synthesized pumps account for* 25% of active pumps daily [2]. Nocturnally synthesized pumps are not inhibited by PPIs given either once or twice daily due to the short (60–90 min) plasma t1/2 of the drug. Together, these processes contribute to a slow onset of acid inhibition, with* 40% inhibition of the pumps with the first dose and* 70 or 80% at steady state after 3 days of treatment at either once a day or twice a day dosing, respectively [3].PPIs are metabolized in the liver by cytochrome CYP2C19 [4], polymorphisms of which affect the pharmacokinetics and pharmacodynamics of the medication. The phenotypes of the CYP2C19 polymorphisms are extensive or rapid metabolizers (RM), intermediate metabolizers (IM), and poor metabolizers (PM)[5]. The plasma ‘‘dwell time’’of a single dose of omeprazole is directly correlated with the rate of metabolism among the different alleles with PM [IM [RM, which in turn affects the level of acid inhibition, again with PM [IM [RM. The rate of metabolism affects the rate of healing of mucosal breaks in GERD patients, with RMs having the lowest cure rate and PMs the highest (RM\IM\PM). The difference in the rate of metabolism also influences the efficacy of H. pylori eradication, since the rate of eradication correlates well with the degree of acid inhibition. Although PPIs are superior to the H2RAs in terms of acid inhibition, there is still a need for a more potent, faster-acting acid inhibitor for better symptom relief and for mucosal healing. An alternative mechanism of inhibition of the gastric H+, K+-ATPase was discovered during studies of dihydropyridine-based Ca2+ channel blockers (CCBs), which
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CYP2C19 药物遗传学对基于质子泵抑制剂的幽门螺杆菌根除疗法的治疗影响。
DOI：
10.1358/mf.2003.25.2.723687
发表时间：
2003
影响因子：
--
作者：
T. Furuta;N. Shirai;K. Ohashi;T. Ishizaki
通讯作者：
T. Ishizaki
DOI：
10.1016/s0021-9258(18)61620-5
发表时间：
1987-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
B. Wallmark;Carin BrivingS;Jan FryklundS;Keith MunsonQ;Raymond Jacksons;John MendleinQ;Edd RabonQ;George SachsQ
通讯作者：
B. Wallmark;Carin BrivingS;Jan FryklundS;Keith MunsonQ;Raymond Jacksons;John MendleinQ;Edd RabonQ;George SachsQ
影响因子：
3.1
作者：
Matsukawa, Jun;Kogame, Akifumi;Inatomi, Nobuhiro
通讯作者：
Inatomi, Nobuhiro
影响因子：
3.2
作者：
CEDERBERG, C;LIND, T;OLBE, L
通讯作者：
OLBE, L