Nakano S, Watanabe H, Nagai K, Ogawa N
Clin Pharmacol Ther. 1984 Aug;36(2):271-7. doi: 10.1038/clpt.1984.174.
The effect of dosing time on diazepam kinetics was investigated in 28 healthy men. A 5-mg dose of diazepam was given orally or intravenously on two occasions, in the morning (9:30 A.M.) or in the evening (9:30 P.M.) under the postprandial condition or after a 9-hr fast. After oral doses under postprandial conditions, the mean peak total diazepam concentration in plasma was higher and the time to peak concentration was faster after morning dosing than after evening dosing, but neither mean elimination t1/2 nor AUC between morning and evening dosings differ. Intravenous diazepam did not eliminate the time-dependent changes in diazepam kinetics occurring soon after injection under postprandial conditions, although it diminished the difference. During the 9-hr fast, time-dependent changes in diazepam kinetics were marked, especially after intravenous injection. Diazepam free fraction was lower 0.5 hr after intravenous dosing in the morning, and there was a negative correlation (r = -0.678) between the diazepam free fraction and total diazepam plasma concentration. These results suggest that diurnal variations in rate of drug distribution because of alterations in protein binding as well as in absorption from the gastrointestinal tract contribute to time-dependent changes in diazepam kinetics.
在28名健康男性中研究了给药时间对地西泮药代动力学的影响。在餐后状态或禁食9小时后，于上午（9:30）或晚上（9:30）两个时间点分别口服或静脉给予5mg地西泮。餐后状态下口服给药后，上午给药时血浆中地西泮总浓度的平均峰值较高，达峰时间较晚上给药更快，但上午和晚上给药之间的平均消除半衰期和药时曲线下面积均无差异。静脉注射地西泮虽然减小了差异，但并未消除餐后状态下注射后不久出现的地西泮药代动力学的时间依赖性变化。在禁食9小时期间，地西泮药代动力学的时间依赖性变化很明显，尤其是静脉注射后。上午静脉给药后0.5小时地西泮游离分数较低，且地西泮游离分数与地西泮血浆总浓度之间存在负相关（r = -0.678）。这些结果表明，由于蛋白质结合改变以及胃肠道吸收改变导致的药物分布速率的昼夜变化，促成了地西泮药代动力学的时间依赖性变化。
