氢化阿托酸在大鼠体内立体选择性时间药代动力学

以余弦法分析氢化阿托酸(HTA)药代动力学参数证明,下列参数具有昼夜节律:标准明暗周期下,S(+)-HTA的T_1/2β和CL,R(-)-HTA的T_1/2β以及外消旋体的CL和MRT;反相明暗周期下,S(+)-HTA的T_1/2β和AUC,R(-)-体的CL以及外消旋体的CL。下列参数具有立体选择昼夜节律:标准明暗周期下,S(+)-HTA的CL,反相明暗周期下,S(+)-HTA的T_1/2β和AUC以及R(-)-HTA的CL。以外消旋体给药后,大鼠体内由R(-)-体向S(+)-体的转化过程,可出现昼夜节律,在两种明暗周期下,峰值相位均位于黑暗期之末,据此,提出HTA的清晨给药治疗方案。

STEREOSELECTIVE CHRONOPHARMACOKINETICS OF HYDRATROPIC ACID IN RATS

The circadian rhythms of hydratropic acid (HTA) pharmacokinetic parameters were studied by using consinor method. Under standard light—dark cycle, the T_1/2β and CL of S(+)-HTA, T_1/2βof R(—)-HTA and CL, MRT of RS (±)-HTA were found to have circadian rhythm. Circadian rhythms were also found in the T_1/2 β and AUC of S (+)-HTA, CLS of R(—)-HTA and RS (±)-HTA under reverse light—dark cycle. Stereoselective circadian rhythms were found in CL of S(+)-HTA under standard light—dark cycle and in T_1/2β and AUC of S(+)-HTA and CL of R(—)-HTA under reverse light—dark cycle. After ip administration of RS(±)-HTA to rat under two different light—dark cycles, the peak phases of circadian rhythms in the biotransformation of R (—)-HTA to S (+)-HTA in rat were both at the end of the dark phase. This suggests that administration of the drug at early morning is a recommendable scheme for chronotherapy with HTA.