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 ig T-614 原料 5、10和20 mg/kg 的药代动力学（吸收、分布、代谢、排泄、蛋白结合率）及 Beagle 犬po T-614 原料及片剂（5 mg/kg）的相对生物利用度研究；采用 LC/MS/MS 方法对大鼠 ig T-614 原料 50 mg/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 ig T-614 原料 5、10和20 mg/kg 后主要药动学参数t_1/2Ke 分别为（5.41 ± 1.28）、（4.31 ± 0.48）和（4.17 ± 1.04）h，t_1/2Ka 分别为（0.16 ± 0.06）、（0.30 ± 0.19）和（0.58± 0.37）h，t_max 分别为（0.81 ± 0.20）、（1.16 ± 0.60）和（1.78 ± 0.61）h，C_max 分别为（7.83 ± 1.85）、（15.46 ± 2.27）和（30.89 ± 6.54）μg/mL，AUC_0～t 分别为（72.08 ± 11.05）、（127.53 ± 17.68）和（296.24 ± 57.10）μg /mL · h；大鼠 ig T-614 原料 10 mg/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 ig T-614 原料 10 mg/kg 72 h 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20 μg/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 5 mg/kg，其主要药动学参数t_1/2Ke 分别为（11.10 ± 1.50）和（9.30 ± 3.29）h，t_1/2Ka 分别为（1.18 ± 0.22）和（1.53 ± 1.26）h，t_max 分别为（4.24 ± 0.48）和（4.23 ± 1.75）h，C_max 分别为（0.77 ± 0.13）和（1.01 ± 0.27）μg/mL，AUC_0～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 ig 50 mg/kg T-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 20～0.009 1 μmol/L 时，对 CYP2D6、CYP1A2、CYP2C9、CYP2C19 和 CYP3A4 活力抑制的 IC₅₀>20 μmol/L。结论：大鼠 ig T-614 原料 5、10 和 20 mg/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 t_1/2Ke was（5.41 ± 1.28）,（4.31 ± 0.48）, and（4.17 ± 1.04）h^-1; t_1/2Ka was（0.16 ± 0.06）,（0.30 ± 0.19）, and（0.58 ± 0.37）h^-1; t_max was（0.81 ± 0.20）,（1.16 ± 0.60）, and（1.78 ± 0.61）h, C_max was（7.83 ± 1.85）,（15.46 ± 2.27）, and（30.89 ± 6.54）μg/mL, AUC_0~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, t_1/2Ke was（11.10 ± 1.50）and（9.30 ± 3.29）h, t_1/2Ka（1.18 ± 0.22）and（1.53 ± 1.26）h, t_max（4.24 ± 0.48）and（4.23 ± 1.75）h, C_max（0.77 ± 0.13）and（1.01 ± 0.27）μg/mL, and AUC_0~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.