摘要
目的:研究T-614原料在动物体内的吸收、分布、代谢、排泄、蛋白结合及口服原料和片剂的相对生物利用度;研究T-614原料对5种人P450同工酶的体外抑制作用。方法:采用HPLC方法进行大鼠igT-614原料5、10和20mg/kg的药代动力学(吸收、分布、代谢、排泄、蛋白结合率)及Beagle犬poT-614原料及片剂(5mg/kg)的相对生物利用度研究;采用LC/MS/MS方法对大鼠igT-614原料50mg/kg后尿液中的主要代谢转化产物进行了分析;采用高通量P450酶抑制剂筛选试剂盒测定了T-614原料对人P450同工酶CYP2D6、CYP1A2、CYP2C9、CYP2C19和CYP3A4的体外抑制活性。结果:大鼠igT-614原料5、10和20mg/kg后主要药动学参数t1/2Ke分别为(5.41±1.28)、(4.31±0.48)和(4.17±1.04)h,t1/2Ka分别为(0.16±0.06)、(0.30±0.19)和(0.58±0.37)h,tmax分别为(0.81±0.20)、(1.16±0.60)和(1.78±0.61)h,Cmax分别为(7.83±1.85)、(15.46±2.27)和(30.89±6.54)μg/mL,AUC0~t分别为(72.08±11.05)、(127.53±17.68)和(296.24±57.10)μg/mL·h;大鼠igT-614原料10mg/kg后在所有脏器组织中均能检测到原形物质,其中肝、肾、子宫的量最高,脑的量最低;大鼠igT-614原料10mg/kg72h后,粪中的排泄率达到15.75%,而尿与胆汁的排泄率分别为0.836%和0.677%;当质量浓度为5、10和20μg/mL时,T-614原料的蛋白结合率分别为(17.2±5.1)%、(28.6±7.1)%和(28.9±10.2)%,平均蛋白结合率为(24.9±9.2)%。Beagle犬口服T-614原料和片剂5mg/kg,其主要药动学参数t1/2Ke分别为(11.10±1.50)和(9.30±3.29)h,t1/2Ka分别为(1.18±0.22)和(1.53±1.26)h,tmax分别为(4.24±0.48)和(4.23±1.75)h,Cmax分别为(0.77±0.13)和(1.01±0.27)μg/mL,AUC0~t分别为(12.69±2.77)和(16.81±6.49)μg/mL·h;微粉化片剂相对于原料的相对生物利用度为132.5%。大鼠ig50mg/kgT-614后,尿液中检测到T-614的5种主要代谢物,包括T-614原结构的异构体、苯环羟基化、脱醛基后再羟基化、脱醛基后胺基乙酰化、脱醛基后的产物。体外CYP450酶活性抑制试验结果表明,T-614原料浓度为20~0.0091μmol/L时,对CYP2D6、CYP1A2、CYP2C9、CYP2C19和CYP3A4活力抑制的IC50】20μmol/L。结论:大鼠igT-614原料5、10和20mg/kg剂量的药代动力学特征符合一级吸收。在大鼠体内各组织中分布较广,蛋白结合率低于30%。粪、尿、胆汁中原形物质的总排泄量低于20%。Beagle犬口服T-614片剂的相对生物利用度为132.5%。T-614对人P450同工酶CYP2D6、CYP1A2、CYP2C9、CYP2C19和CYP3A4活力无抑制作用。T-614在肾脏中代谢转化的主要产物为原形物质的异构化、羟基化、脱醛基后再羟基化、脱醛基后胺基乙酰化、脱醛基等。
Objective: To study the absorption, distribution, excretion, metabolism, and protein bounding of raw material in vivo of animals and relative bioavailability of T-614 orally raw materials and tablets and the inhibitory activities of T-614 to 5 kinds P450 Isodynamic enzymes. Methods: Use HPLC method to carry out pharmacokinetics of T-614 in rats at doses of 5, 10 and 20 mg/kg, and also use the same method to observe the relative bioavailability of T-614 micro-powder tablets by po administered 5 mg/kg to Beagle dog. Using LC/MS/MS method to analyze the metabolites of T-614 50 mg/kg in urine of rats. Using P450 High throughput Inhibitor Screening Kit to determine the inhibitory activities of T-614 to P450 enzymes, CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP3A4. Results: After ig administration of T-614(5, 10, and 20 mg/kg)to rats, the main pharmacokinetic parameters t1/2Ke was(5.41 ± 1.28),(4.31 ± 0.48), and (4.17 ± 1.04)h-1; t1/2Ka was(0.16 ± 0.06)(,0.30 ± 0.19), and(0.58 ± 0.37)h-1; tmax was(0.81 ± 0.20)(,1.16 ± 0.60), and(1.78 ± 0.61)h, Cmax was(7.83 ± 1.85),(15.46 ± 2.27), and(30.89 ± 6.54)μg/mL, AUC0~t was(72.08 ± 11.05), (127.53 ± 17.68), and(296.24 ± 57.10)μg /mL·h, respectively. After ig T-614(10 mg/kg)to rats, T-614 in all organic tissues was observed, contents in liver and kidney were the maximum, and the minimum in brain. During 72 h after administration of T-614(10 mg/kg), excretion amount was 15.75 % from faeces, but only 0.836 % and 0.677 % from urine and bile, respectively. At 5 , 10, and 20 μg/mL, the protein bounding rate of T-614 was(17.2 ± 5.1)%,(28.6 ± 7.1)%, and(28.9 ± 10.2)%,respectively. The average value was(24.9 ± 9.2)%. After 5 mg/kg with po administration of T-614 and the tablets in Beagle dog, t1/2Ke was (11.10 ± 1.50) and (9.30 ± 3.29)h, t1/2Ka(1.18 ± 0.22)and(1.53 ± 1.26)h, tmax(4.24 ± 0.48)and(4.23 ± 1.75)h, Cmax(0.77 ± 0.13)and(1.01 ± 0.27)μg/mL, and AUC0~t (12.69 ± 2.77) and (16.81 ± 6.49) μg/mL·h, respectively. The relative bioavailability of T-614 tablets was 132.5 %. Metabolites of T-614 in the urine were found to have five kinds of metabolic products, including isomer, hydrogenation, dealdehydelation, and hydrogenation and amino-acetylation of dealdehydelation products of T-614. At 20-0.009 1 μmol/L of T-614, the IC50 was over 20 μmol/L to CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP3A4. Conclusion: After ig administration of T-614(5, 10, and 20 mg/kg)to rats, the results indicate that pharmacokinetic study shows first order kinetic characteristics, distribution is broader in every tissue of rats, protein bounding rate is lower, and total excretion amounts are lower in urine and bile. Oral relative bioavailability of the T-614 tablets in Beagle dog is 132.5%. T-614 has no inhibitory action to P450 enzymes (CYP2D6, CYP1A2, CYP2C9, CYP2C19, and CYP3A4). The main metabolism transformation is isomer, hydrogenation, dealdehydelation and hydrogenation and amino-acetylation of dealdehydelation products of T-614.
出处
《药物评价研究》
CAS
2009年第1期19-28,共10页
Drug Evaluation Research
