质子泵抑制剂奥美拉唑和泮托拉唑抑制期间胃酸分泌与质子泵活性之间的相关性。

Nishioka K, Nagao T, Urushidani T

Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan.

Biochem Pharmacol. 1999 Oct 15;58(8):1349-59. doi: 10.1016/s0006-2952(99)00211-7.

Omeprazole and pantoprazole are known to be irreversible, SH-acting inhibitors of gastric H+,K+-adenosine triphosphatase (H+,K+-ATPase). Both drugs concentration-dependently and pH-dependently inhibited K+-dependent p-nitrophenyl phosphatase (K+-pNPPase) activity in purified rabbit gastric microsomes. The potency of omeprazole was about three times that of pantoprazole in the pH ranges tested. Both drugs also inhibited acid secretion, as determined by [14C]aminopyrine accumulation in isolated rabbit gastric glands, with the potency ratio being about 5 (omeprazole over that of pantoprazole). Under conditions in which acid secretion was inhibited completely by the drugs, the total K+-pNPPase activity in the digitonin-permeabilized glands was scarcely reduced, showing an apparent discrepancy between the acid secretion and the proton pump activity. The isolated glands were stimulated with secretagogues for 30 min in the presence of the inhibitors, homogenized, and then separated into fractions in which K+-pNPPase activity was measured. Omeprazole exclusively inhibited the activity in the low-speed fraction, which was rich in the apical membranes, whereas pantoprazole did not inhibit activity in any fraction. When the time of treatment with the inhibitors was increased up to 5 hr, the inhibition of the total K+-pNPPase activity in the glands reached a plateau at an inhibition rate lower than 50% within 2 hr. This suggested that no continuous recycling of the proton pump was occurring during stimulation. The inhibitory effect of both drugs on the permeabilized gland preparation was less potent than that on the purified enzyme, especially at the higher pH, and it appeared to be partially reversible. The extent of the reduction in potency was more prominent for pantoprazole. It is concluded that a lower amount of proton pump activity needs to be inhibited by pantoprazole than by omeprazole to achieve the same extent of acid secretion inhibition. This appears to be due to the nature of pantoprazole, i.e. the requirement of low pH for activation and the partial reversibility of the inhibition.

已知奥美拉唑和泮托拉唑是胃H⁺，K⁺ - 腺苷三磷酸酶（H⁺，K⁺ - ATP酶）的不可逆性、作用于巯基的抑制剂。两种药物在纯化的兔胃微粒体中均呈现浓度依赖性和pH依赖性地抑制K⁺依赖性对硝基苯磷酸酶（K⁺ - pNPP酶）活性。在测试的pH范围内，奥美拉唑的效力约为泮托拉唑的三倍。两种药物还抑制胃酸分泌，这通过[¹⁴C]氨基比林在分离的兔胃腺中的积累来确定，效力比约为5（奥美拉唑相对于泮托拉唑）。在药物完全抑制胃酸分泌的条件下，洋地黄皂苷通透化腺中的总K⁺ - pNPP酶活性几乎没有降低，表明胃酸分泌与质子泵活性之间存在明显差异。在抑制剂存在的情况下，用促分泌剂刺激分离的腺体30分钟，然后匀浆，接着分离成测量K⁺ - pNPP酶活性的组分。奥美拉唑仅抑制富含顶端膜的低速组分中的活性，而泮托拉唑在任何组分中均不抑制活性。当抑制剂处理时间延长至5小时时，腺体中总K⁺ - pNPP酶活性的抑制在2小时内以低于50％的抑制率达到平台期。这表明在刺激过程中没有发生质子泵的持续循环。两种药物对通透化腺体制剂的抑制作用比其对纯化酶的抑制作用弱，尤其是在较高pH时，并且似乎是部分可逆的。泮托拉唑效力降低的程度更为显著。结论是，与奥美拉唑相比，泮托拉唑需要抑制较低量的质子泵活性以达到相同程度的胃酸分泌抑制。这似乎是由于泮托拉唑的性质，即激活需要低pH以及抑制的部分可逆性。