Ferron G M, McKeand W, Mayer P R
Wyeth-Ayerst Research, 145 King of Prussia Road, Radnor, PA 19087, USA.
J Clin Pharmacol. 2001 Feb;41(2):149-56. doi: 10.1177/00912700122009953.
The relationship between the pharmacokinetics of pantoprazole, an irreversible proton pump inhibitor, and its effect on gastric acid secretion was evaluated in humans and rats. Pantoprazole pharmacokinetics were studied in 6 rats (5 mg/kg, i.v.) and 22 healthy volunteers (10 to 80 mg, i.v. and oral). Gastric acid secretion under maximum pentagastrin stimulation was measured after i.v. administration of placebo or pantoprazole in 31 rats (0.12 to 1.15 mg/kg) for 4 hours and in 31 subjects (20 to 120 mg) for 24 hours. Pantoprazole has short half-lives of 0.5 hours in rats and 0.8 hours in humans. After administration of the highest dose, acid secretion was fully inhibited within 1 hour and for the whole observation period in both species. An irreversible pharmacodynamic response model was successfully developed and validated. The apparent reaction rate constants of pantoprazole with the proton pumps were 0.691 L/mg/h in rats and 0.751 L/mg/h in humans, and the apparent recovery rates of the pumps were 0.053 h-1 and 0.031 h-1, respectively. The maximum inhibition and the overall effect of pantoprazole are related to exposure, and the onset is related to initial pantoprazole concentrations. It was concluded that this irreversible response model accurately describes the effect of i.v. and oral pantoprazole on gastric secretion and may be used to predict effects under other dosage regimens.
在人和大鼠中评估了不可逆质子泵抑制剂泮托拉唑的药代动力学及其对胃酸分泌的影响。在6只大鼠（静脉注射5mg/kg）和22名健康志愿者（静脉注射和口服10至80mg）中研究了泮托拉唑的药代动力学。在31只大鼠（0.12至1.15mg/kg）静脉注射安慰剂或泮托拉唑4小时以及31名受试者（20至120mg）静脉注射24小时后，测量了最大五肽胃泌素刺激下的胃酸分泌。泮托拉唑在大鼠中的半衰期较短，为0.5小时，在人类中为0.8小时。给予最高剂量后，两种物种在1小时内及整个观察期内胃酸分泌均被完全抑制。成功建立并验证了不可逆药效学反应模型。泮托拉唑与质子泵的表观反应速率常数在大鼠中为0.691L/mg/h，在人类中为0.751L/mg/h，质子泵的表观恢复率分别为0.053h-1和0.031h-1。泮托拉唑的最大抑制作用和总体效应与暴露量有关，起效与初始泮托拉唑浓度有关。得出的结论是，这种不可逆反应模型准确描述了静脉注射和口服泮托拉唑对胃分泌的影响，可用于预测其他给药方案下的效应。
