目的 研究昼夜不同时间用药, 氨氯地平在大鼠体内药动学变化, 探讨氨氯地平的时间药动学的影响因素, 为临床合理用药提供参考。方法 SD雄性大鼠随机分成2组, 于8:00及20:00灌胃给予氨氯地平(1 mgkg-1), 于给药前及给药后0.33、0.67、1、2、4、8、12及24 h眼内眦静脉取血。HPLC-MS-MS测定血浆氨氯地平浓度。结果 氨氯地平在大鼠体内ρ-t曲线用统计矩法拟合。氨氯地平吸收缓慢, MRT(47.52±3.12)h(8:00用药)。MRT(53.34±4.00)h(20:00用药)。昼夜不同时间用药, 对氨氯地平药动学影响很大。与8:00用药组相比, 20:00用药组血药浓度显著升高(P<0.01), ρmax及AUC显著增大(P<0.01), CL/F显著降低(P<0.01), 且ρmax、AUC0-t、MRT0-t昼夜间用药差异有统计学意义(P<0.05), 晚间给药ρmax是上午给药的(3.26±1.82)倍, AUC0-t是上午给药的(4.53±3.20)倍, 晚上给药MRT0-t比上午给药要延长(5.83±2.53)h。结论 氨氯地平8:00用药, 血药浓度较低, ρmax及AUC较小, CL/F及Vd/F较大;20:00用药则相反。氨氯地平片对大鼠昼夜不同时间用药对其药动学有一定影响。
Abstract
OBJECTIVE To study the influence of circadian dosing time on pharmacokinetics of amlodipine in rats and to assess possible pharmacokinetic interactions.METHODS Twelve male SD rats were divided into two groups, and a single dose of amlodipine (1 mgkg-1) were given intragastrically at either 8 00 or 20 00, respectively.Plasma samples were collected at 0, 0.33, 0.67, 1, 2, 4, 8, 12 and 24 h after drug administration. A HPLC-MS-MS detection method were developed to determine amlodipine concentrations in plasma.RESULTS Absorption of amlodipine in rat was very slowly with MRT0-t about 12 h. Dosing time schedule influnced the pharmacokinetics of amlodipine dramatically and showed higher plasma drug levels (P<0.01), larger AUC (P<0.01) and lower CL/F (P<0.01) when dosing at 20 00 compared with that at 8 00 group.The difference of drug use between ρmax, AUC0-t and MRT0-t was statistically significant (P<0.05).The ρmax is three times as large as the morning medicine, AUC is four times as large as the drug in the morning.In the evening, MRT is extended for five hours longer than in the moring.CONCLUSION The amlodipine plasma drug concentrations are lower, and CL/F, Vd/F are larger when dosing at 8 00 than those at 20 00.The administration of amlodipine at different times of a day shows a certain effect on the pharmacokinetics of amlodipine.
关键词
氨氯地平 /
药动学 /
昼夜节律
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Key words
amlodipine /
pharmacokinetics /
circadian rhythm
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中图分类号：
R969.1
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