褪黑素在非杓型自发性高血压大鼠体内的时辰药动学研究

Chronopharmacokinetics of melatonin in non-dipper spontaneous hypertension rats

目的:研究褪黑素(melatonin,MEL)在非杓型自发性高血压大鼠(spontaneously hypertensive rat,SHR)体内时辰药动学差异。方法:建立MEL的HPLC检测方法,并考察方法的专属性、精密度、回收率、稳定性。12只非杓型雄性SHR大鼠随机分为两组,于08∶00和20∶00灌胃给与MEL(20 mg/kg),于给药前后5、10、15、20、30、40、60、90、120、240、360 min眼眶取血,荧光HPLC法测定血浆MEL浓度。结果:本研究建立的MEL检测方法专属性、精密度、回收率和稳定性均符合生物分析方法指导原则要求,证明该方法成熟可靠。MEL在08∶00给药Tmax约19 min,但在20∶00给药Tmax约32 min(P<0.01);08∶00组大鼠Cmax、AUC、T1/2显著高于20∶00组大鼠(P<0.05,P<0.01);20∶00组大鼠药动参数CL显著高于08∶00组大鼠(P<0.05)。结论:昼夜不同时间用药对MEL在非杓型SHR大鼠体内药动学具有一定程度的影响,本研究从药代动力学角度部分阐明MEL恢复血压节律的机制,为临床合理用药提供理论基础。

AIM:To study the chronological pharmacokinetic differences of melatonin(MEL)in non-dipper spontaneously hypertensive rats(SHR).METHODS:The HPLC detection method of MEL was established,and the specificity,precision,recovery rate and stability of the method were examined.Twelve male SD rats were divided into two groups,and a single dose of MEL(20 mg/kg)was given intragastrically at either 08∶00 or 20∶00,respectively.Plasma samples were collected at 0,5,10,15,20,30,40,60,90,120,240,360 min after drug administration,and the plasma MEL concentration was determined by fluorescence HPLC.RESULTS:The specificity,precision,recovery rate and stability of the MEL detection method established in this study were in line with the requirements of the biological analysis method guidelines,proving that the method was mature and reliable.After MEL was administered at 08∶00,the Tmax could be reached in about 19 min.However,in 20∶00 group rats,it took about 32 min to reach Tmax(P<0.01).Cmax,AUC,T1/2 in 08∶00 group rats were significantly higher than that of rats in 20∶00 group(P<0.05,P<0.01).The pharmacokinetic parameters CL in the 20∶00 group rats were significantly higher than 08∶00 group rats(P<0.05).CONCLUSION:Medication at different times of day and night has a certain degree of influence on the pharmacokinetics of MEL in non-dipper SHR rats.From the perspective of pharmacokinetics,the mechanism of MEL restoring blood pressure rhythm is partly elucidated,which provides a theoretical basis for the rational use of drugs in clinic.