新型Rho激酶抑制剂DL0805-1大鼠体内药代动力学初步研究  

Preliminary study on pharmacokinetics of DL0805-1:a novel Rho kinase inhibitor in rats

作　　者：武玉洁[1] 王夙博[1] 袁天翊[1] 李人则 焦晓臻[2] 谢平[2] 方莲花[1] 杜冠华[1,2] 

机构地区：[1]中国医学科学院北京协和医学院药物研究所药物靶点研究与新药筛选北京市重点实验室,北京100050 [2]中国医学科学院北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室,北京100050

出　　处：《中国药理学通报》2014年第8期1171-1174,共4页Chinese Pharmacological Bulletin

基　　金：国家科技部“重大新药创制”科技重大专项资助项目(No2013ZX09103-001-008,2012ZX09103-101-078)

摘　　要：目的建立一种高效液相色谱法(high performance liquid chromatography,HPLC)测定具有Rho激酶抑制作用的吲唑类化合物DL0805-1在大鼠血浆中血药浓度的方法,并用该法研究DL0805-1的药物代谢动力学。方法检测系统为Agilent 1200-DAD;色谱柱:Agilent TC-C18(4.6 mm×250mm,5μm);检测波长:235 nm;柱温:35℃;流速:1 ml·min-1;流动相:乙腈与0.05%H3PO4梯度洗脱;尾静脉给予大鼠DL0805-1,于不同时间点取血,测定血浆中DL0805-1的浓度并计算其药物代谢动力学参数。结果尾静脉给予DL0805-1后,在血浆中检测到原型及其代谢产物。其中,DL0805-1的半衰期为(2.34±1.42)h,达峰浓度为(3.51±0.44)mg·L-1,代谢产物半衰期为(1.27±0.45)h,达峰浓度为(3.55±0.22)mg·L-1。结论 DL0805-1在体内可能代谢成其它物质发挥生物学作用。该法灵敏度高,操作简便、准确,可用于大鼠血浆中DL0805-1的测定及药动学研究。Aim ToestablishthemethodofHighper-formance liquid chromatography （ HPLC ） for detecting plasma concentration of indazole compound DL0805-1 , a Rho kinase inhibitor, and to investigate its pharma-cokinetics in rats with intravenous injection. Methods ThedetectingsystemwasAgilent1200-DAD;chro-matographic column was Agilent TC-C18 （ 4. 6 mm ＆#215; 250 mm, 5 μm）; the ultraviolet detection wavelength was 235 nm; the column temperature was 35 ℃; the flow rate was 1 ml·min-1;the mobile phase was ace-tonitrile-0. 05% H3 PO4 gradient elute. Rat blood sam-ples were collected at different intervals after intrave-nous injection of a single dose of DL0805-1 , and the concentration of DL0805-1 in rat plasma were deter-mined by HPLC method for estimating pharmacokinetic parameters.Results Afterintravenousinjectionof DL0805-1 in rats, prototype and its metabolite were detected in plasma. T1/2 of DL0805-1=（2. 34 ± 1. 42） h, Cmax=（3. 51 ± 0. 44） mg·L-1, T1/2 of metabolite of DL0805-1 = （ 1. 27 ± 0. 45 ） h, Cmax = （ 3. 55 ± 0.22）mg·L-1.Conclusion Theseresultssuggest that DL0805-1 may be metabolized into another sub-stance in vivo and play biological functions. The meth-od is sensitive, simple, and accurate, and can be used for the determination of DL0805-1 in rat plasma and pharmacokinetic studies.

关 键 词：DL0805-1 吲唑类化合物 RHO激酶 高效液相色谱法 血药浓度 药代动力学 

分 类 号：R-332[医药卫生]