渗透压微泵恒速给药丙戊酸在小鼠体内的时间药物动力学

以渗透压微泵植入小鼠皮下恒速给予丙戊酸钠，在达到理论稳态浓度时间后，血浆药浓呈昼夜变化，白昼高于夜间，峰值位于明期末。药动学研究揭示丙戊酸血药浓度的昼夜差异可能与其清除率及分布容积的昼夜变化有关。

Chronopharmacokinetics of valproic acid in mice following constant-rate administration by osmotic minipump

The circadian variation in the pharmacokinetics of valproic acid (VPA)following constant-rate and intravenous administration was investigated in mice housed under a light-dark (12:12 h) cycle witn food and water adlibitum.In the constant-rate administration study, osmotic minipumps (VPA 1062.1μg·h￣(-1))were implanted subcutaneously in mice.There was a significant circadian rhythm in the plasma VPA concentrations with higher values in the light phase and lower ones in the dark phase (P<0.01).The clearance of the drug showed a mirror image of circadian rhythm with that of plasma VPA concentrations.There was also asignificant dosing time-dependent change in the kinetics of the drug following an intravenous administration (VPA 50 mg·kg￣(-1)) with higher clearance and larger volume of distribution in mice dosiug at 05:00 than at 17:00.The results suggest that the timing of dosing is important in the kinetics of the drug and that circadian rhythms in the pharmacokinetics of drug can change the plasma drug concentrations to a great extent even if it is at the“steady state”level.