Decktor D L, Pendleton R G, Kellner A T, Davis M A
Rorer Central Research, King of Prussia, Pennsylvania.
J Pharmacol Exp Ther. 1989 Apr;249(1):1-5.
In the rat, treatment with gastric inhibitory drugs may result in hypergastrinemia, an effect thought to be in response to increased gastric pH caused by inhibition of acid secretion. This study compared 24-hr profiles of plasma gastrin levels associated with three different compounds at equivalent, highly effective antisecretory doses. Ranitidine, famotidine and omeprazole at 60, 20 and 40 mg/kg p.o., respectively, inhibited basal acid secretion of chronic gastric fistula rats by greater than 95% and raised intraluminal pH to above 7.0 for 5 hr. The peak plasma gastrin levels associated with each agent were observed 5 hr after dosing. Ranitidine, famotidine and omeprazole induced statistically significant and distinct peak hypergastrinemic responses of 312 +/- 20, 483 +/- 28 and 616 +/- 27 pg/ml, respectively. After 8 hr ranitidine and famotidine associated gastrin values returned to control levels, whereas those of omeprazole remained substantially above control values until the 12th hr. Differences in peak gastrin levels between compounds disappeared at increased dose levels of 500 mg/kg for ranitidine, 200 or 2000 mg/kg for famotidine and 140 mg/kg for omeprazole. Unlike high dose famotidine, omeprazole (140 mg/kg) maintained peak plasma gastrin levels at 8, 12, and 16 hr after dosing. These studies demonstrate clearly hypergastrinemic responses to single dose administration of ranitidine, famotidine and omeprazole. The differences observed in peak plasma gastrin levels at equivalent antisecretory doses of these agents suggests the presence of luminal acid independent components that effect gastrin release. Moreover, these studies indicate that, in the rat, the most unique aspect of omeprazole-associated hypergastrinemia is the magnitude of its prolonged response.
在大鼠中，使用胃抑制药物治疗可能会导致高胃泌素血症，这种效应被认为是对由于胃酸分泌受抑制导致胃内pH值升高的一种反应。本研究比较了三种不同化合物在等效、高效抗分泌剂量下血浆胃泌素水平的24小时变化情况。雷尼替丁、法莫替丁和奥美拉唑分别以60、20和40mg/kg口服给药，可使慢性胃瘘大鼠的基础胃酸分泌抑制率超过95%，并使管腔内pH值在5小时内升至7.0以上。给药后5小时观察到与每种药物相关的血浆胃泌素水平峰值。雷尼替丁、法莫替丁和奥美拉唑分别诱导出具有统计学意义且明显不同的高胃泌素血症峰值反应，分别为312±20、483±28和616±27pg/ml。8小时后，雷尼替丁和法莫替丁相关的胃泌素值恢复到对照水平，而奥美拉唑的胃泌素值在第12小时之前仍显著高于对照值。当雷尼替丁剂量增加到500mg/kg、法莫替丁剂量增加到200或2000mg/kg、奥美拉唑剂量增加到140mg/kg时，各化合物之间胃泌素峰值水平的差异消失。与高剂量法莫替丁不同，奥美拉唑（140mg/kg）在给药后8、12和16小时维持血浆胃泌素峰值水平。这些研究清楚地证明了雷尼替丁、法莫替丁和奥美拉唑单次给药会引起高胃泌素血症反应。在这些药物等效抗分泌剂量下观察到的血浆胃泌素峰值水平差异表明，存在影响胃泌素释放的腔酸非依赖性成分。此外，这些研究表明，在大鼠中，奥美拉唑相关高胃泌素血症最独特的方面是其延长反应的程度。
