四氢姜黄素及其固体分散体在小鼠体内药动学及相对生物利用度的研究  

Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose

作　　者：廖利[1,2] 华桦[1] 赵军宁[1] 罗恒[1] 杨安东[1] 

机构地区：[1]四川省中医药科学院药理毒理研究所,国家中医药管理局中药质量生物评价重点研究室,四川省道地药材系统开发工程技术研究中心,中药品质评价与创新中药研究四川省重点实验室,四川成都610041 [2]成都中医药大学药学院,四川成都611730

出　　处：《中国中药杂志》2014年第6期1101-1106,共6页China Journal of Chinese Materia Medica

基　　金：国家"重大新药创制"科技重大专项(2011ZX09401-3042-1);国家支撑计划项目(2012BAI29B10);四川省科技支撑计划项目(2013sz0115)

摘　　要：为建立HPLC-MS/MS测定小鼠血浆中四氢姜黄素（THC）浓度的方法，比较四氢姜黄素及其固体分散体在小鼠体内的生物利用度，该实验采用200只SPF级KM小鼠随机分为2组，在禁食状态下口服给药（THC及其固体分散体，剂量均按THC计：400 mg·kg^-1）的方法，通过HPLC-MS/MS系统测定小鼠给予THC及其固体分散体后15，30，45 min，1，1.5，2，3，4，6，24 h血浆中THC的血药浓度，根据药时曲线采用Phoenix WinNonlin软件计算药动学参数并进行数据分析，计算其相对生物利用度（F）：F=AUCTHC固体分散体/AUCTHC×100%。经过方法学考证，THC在9.06-972.00 μg·L^-1线性良好（R2〉0.999），定量下线为2 μg·L^-1，最低检测限为0.7 μg·L^-1，特异性好，无干扰内源性物质，日内和日间精密度≤13%，回收率高且血浆样品稳定性好，表明该测定方法特异、快速、准确、可靠，可满足四氢姜黄素体内药动学研究需要。小鼠口服四氢姜黄素及其固体分散体后的药动学参数如下：Tmax分别为60，15 min，AUC0-t分别为44 500.43 mg·L^-1·min，57 497.81 mg·L^-1·min，AUC0-∞分别为51 226.00 mg·L^-1·min，68 031.48 mg·L^-1·min，MRT0-∞分别为596.915 6 min，661.747 7 min，CLz/F分别为0.007 809 L·min^-1·kg^-1，0.005 88 L·min^-1·kg^-1。与四氢姜黄素相比，其固体分散体的平均滞留时间（MRT）和消除半衰期（t1/2）都略有延长，达峰时间（tmax）明显提前，且AUC0-24 h，AUC0-∞，Cmax均显著提高，其相对生物利用度是四氢姜黄素的1.34倍。通过该实验，建立了准确、灵敏的适用于小鼠血浆THC含量测定的HPLC-MS/MS检测方法；THC固体分散体较THC相比能明显提高小鼠灌胃的生物利用度。To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting （calculate on THC：400 mg·kg^-1）, used HPLC-MS/MS method to determine the THC concentration of each period at the following times： baseline （ predose ）,15,30,45 min,1,1.5,2,3,4,6,24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 μg·L^-1 for THC （R2=0.999）. The limit of detection （LOD） was 0.7 μg·L^-1, respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%,The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions （RSD〈15%）.The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows：Tmax were 60 and 15 min,AUC0-t were 44 500.43 and 57 497.81 mg·L^-1·min,AUC0-∞ were 51 226.00 and 68 031.48 mg·L^-1·min,MRT0-∞ were 596.915 6, 661.747 7 min,CLz/F were 0.007 809 and 0.005 88 L·min^-1·kg^-1. Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the tmax was significantly reduced, AUC0-24 h, AUC0-∞ and Cmax were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative bioavailability of THC-solid dispersion show significant improvement compared to THC.

关 键 词：四氢姜黄素 生物利用度 固体分散体 HPLC—MS MS 

分 类 号：R285.5[医药卫生—中药学]