不同给药途径灯盏乙素及其代谢物在大鼠体内处置差异研究

Comparative study of disposition of scutellarin and its major metabolite with different administration routes in rats

建立液相色谱-串联质谱(LC-MS/MS)法同时测定大鼠血浆和组织中灯盏乙素及其代谢物异灯盏乙素浓度,比较不同给药途径下灯盏乙素和代谢物在大鼠体内处置的差异。大鼠分别经静脉(20 mg·kg^(-1))和灌胃(80 mg·kg^(-1))给予灯盏花素,于给药前和给药后不同时间点取血和主要组织。匀浆处理后,以LC-MS/MS法测定灯盏乙素与异灯盏乙素浓度。测定血浆中灯盏乙素/异灯盏乙素线性范围为10.0/5.00~5 000/2 500 ng·m L^(-1)、各组织中灯盏乙素/异灯盏乙素线性范围为30.0/15.0~10 000/5 000 ng·g^(-1)。所建方法的精密度与准确度、选择性、交叉干扰、基质效应等均符合生物样品的分析要求。静脉给药后,灯盏乙素主要分布于小肠、膀胱和肾脏组织,异灯盏乙素的血浆和组织暴露量不足灯盏乙素暴露量的5%。灌胃给药后,灯盏乙素在大部分组织中暴露量高于血浆暴露量,主要分布于消化道、膀胱、肾上腺和肺组织,异灯盏乙素血浆暴露量高于灯盏乙素,但其组织暴露量明显低于灯盏乙素。建立的LC-MS/MS法适用于大鼠血浆和各组织中的灯盏乙素/异灯盏乙素浓度测定。两种给药方式下,灯盏乙素和异灯盏乙素在大鼠体内分布存在明显差异,灯盏乙素灌胃给药组的组织/血浆暴露比高于静脉给药组,异灯盏乙素组织分布程度低于灯盏乙素。两种给药方式下在脑组织中均可检测到灯盏乙素,但未检测到异灯盏乙素,推测是因为脑组织OATP转运体对灯盏乙素的亲和力远高于异灯盏乙素。

The study was designed to establish an LC-MS/MS method for the simultaneous determination of scutellarin and its major metabolite isoscutellarin in rat tissues and plasma,and to investigate the effect of different route of administration on the tissue distribution of scutellarin and its metabolite in rats.Rats were treated both intravenously and intragastrically with 20 and 80 mg·kg^-1 scutellarin,respectively.Blood and tissues were collected at predetermined intervals.The concentrations of scutellarin and isoscutellarin were determined by a validated LC-MS/MS method.The method was linear in concentration ranges of 10.0/5.00-5 000/2 500 ng·m L^-1 for scutellarin/isoscutellarin in the rat plasma and 30.0/15.0-10 000/5 000 ng·g^-1 in tissues with acceptable accuracy and precision.Data obtained after an intravenous administration of scutellarin to rats showed that the drug was distributed predominantly into the small intestine,bladder and kidney.The exposures of the metabolite isoscutellarin in plasma and tissue were both less than 5%of the parent drug.After an intragastric administration,stomach wall and small intestine were the preferred sites for scutellarin disposition,followed by bladder,adrenal gland and lung at concentrations significantly higher than its plasma concentration.The plasma exposure of isoscutellarin was higher than that of the parent drug,but its tissue exposure was significantly lower than that of scutellarin.The method established in this study was successfully applied to characterization of the tissue profiles of scutellarin and its metabolite in rats.The route of administration has a marked impact on the disposition of scutellarin and its metabolite in rats.Ratios of the tissue to plasma concentrations after intragastric administration were obviously higher than those after intravenous administration.Scutellarin could pass the blood-brain barrier in a marked extent,but isoscutellarin was not detected in the rat brain,which may be attributed to the fact that scutellarin is a higher-affinity substrate for OATP than isoscutellarin.