Mummaneni V, Amidon G L, Dressman J B
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
Pharm Res. 1995 May;12(5):780-6. doi: 10.1023/a:1016284214708.
The plasma concentration-time profiles of cimetidine often exhibit two peaks following oral administration of a single dose in the fasted state, while the concurrent administration of some antacids results in a lower extent as well as rate of absorption. In the present work, absorption of cimetidine after a single dose in the fasted state was studied as a function of gastric pH in male beagle dogs to determine whether gastric pH plays a role in the double peak phenomenon and/or can account for the decrease in bioavailability when antacids are coadministered. The extent of absorption of cimetidine was not influenced significantly by gastric pH, indicating that elevation of gastric pH is not the cause of decreases in the bioavailability of cimetidine when it is administered with antacids. Distinct double peaks or plateaux were noted in 8 of 10 plasma profiles when the gastric pH was 3 or below. Irregular absorption behavior was observed in 2 of 6 profiles in the pH range of 3 to 5, while single peaks were observed in all 10 profiles when the gastric pH was maintained at pH > or = 5. It was concluded that gastric pH is a major factor in the generation of cimetidine double peaks. Changes in gastric pH also resulted in changes in the apparent kinetics of absorption. Below pH 5, absorption mostly followed zero-order kinetics (9 of 16 profiles) or a more complex kinetic process involving at least two components to the absorption phase (5 of 16 profiles). At gastric pH > or = 5, however, absorption followed first order kinetics in 7 of 10 profiles. These differences in kinetics of absorption are postulated to arise from variations in gastric emptying as a function of pH and/or carryover effects of gastric pH into the upper intestine.
在禁食状态下单次口服西咪替丁后，其血浆浓度 - 时间曲线通常会出现两个峰值，而同时服用某些抗酸剂会导致吸收程度和吸收速率降低。在本研究中，研究了禁食状态下单剂量西咪替丁在雄性比格犬体内的吸收情况与胃pH值的关系，以确定胃pH值是否在双峰现象中起作用，以及/或者能否解释同时服用抗酸剂时生物利用度的降低。西咪替丁的吸收程度不受胃pH值的显著影响，这表明胃pH值升高不是西咪替丁与抗酸剂合用时生物利用度降低的原因。当胃pH值为3或更低时，10个血浆曲线中有8个出现明显的双峰或平台期。在pH值为3至5的范围内，6个曲线中有2个观察到不规则的吸收行为，而当胃pH值维持在pH≥5时，所有10个曲线均观察到单峰。得出的结论是，胃pH值是西咪替丁双峰产生的主要因素。胃pH值的变化也导致了吸收表观动力学的变化。在pH值低于5时，吸收大多遵循零级动力学（16个曲线中的9个）或涉及吸收阶段至少两个成分的更复杂的动力学过程（16个曲线中的5个）。然而，在胃pH值≥5时，10个曲线中有7个遵循一级动力学。据推测，这些吸收动力学的差异是由于胃排空随pH值变化以及/或者胃pH值对上部肠道的残留效应所致。
