目的：研究 T-614 原料在動物體內(nèi)的吸收、分布、代謝、排泄、蛋白結(jié)合及口服原料和片劑的相對生物利用度；研究 T-614 原料對5種人 P450 同工酶的體外抑制作用。方法：采用 HPLC 方法進行大鼠 ig T-614 原料 5、10和20 mg/kg 的藥代動力學（吸收、分布、代謝、排泄、蛋白結(jié)合率）及 Beagle 犬po T-614 原料及片劑（5 mg/kg）的相對生物利用度研究；采用 LC/MS/MS 方法對大鼠 ig T-614 原料 50 mg/kg 后尿液中的主要代謝轉(zhuǎn)化產(chǎn)物進行了分析；采用高通量 P450 酶抑制劑篩選試劑盒測定了 T-614 原料對人 P450 同工酶 CYP2D6、CYP1A2、CYP2C9、CYP2C19 和 CYP3A4 的體外抑制活性。結(jié)果：大鼠 ig T-614 原料 5、10和20 mg/kg 后主要藥動學參數(shù)t_1/2Ke 分別為（5.41 ± 1.28）、（4.31 ± 0.48）和（4.17 ± 1.04）h，t_1/2Ka 分別為（0.16 ± 0.06）、（0.30 ± 0.19）和（0.58± 0.37）h，t_max 分別為（0.81 ± 0.20）、（1.16 ± 0.60）和（1.78 ± 0.61）h，C_max 分別為（7.83 ± 1.85）、（15.46 ± 2.27）和（30.89 ± 6.54）μg/mL，AUC_0～t 分別為（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 后在所有臟器組織中均能檢測到原形物質(zhì)，其中肝、腎、子宮的量最高，腦的量最低；大鼠 ig T-614 原料 10 mg/kg 72 h 后，糞中的排泄率達到 15.75 %，而尿與膽汁的排泄率分別為 0.836 %和 0.677 %；當質(zhì)量濃度為 5、10和20 μg/mL 時，T-614 原料的蛋白結(jié)合率分別為（17.2 ± 5.1）%、（28.6± 7.1）%和（28.9 ± 10.2）%，平均蛋白結(jié)合率為（24.9 ± 9.2）%。Beagle 犬口服 T-614 原料和片劑 5 mg/kg，其主要藥動學參數(shù)t_1/2Ke 分別為（11.10 ± 1.50）和（9.30 ± 3.29）h，t_1/2Ka 分別為（1.18 ± 0.22）和（1.53 ± 1.26）h，t_max 分別為（4.24 ± 0.48）和（4.23 ± 1.75）h，C_max 分別為（0.77 ± 0.13）和（1.01 ± 0.27）μg/mL，AUC_0～t 分別為（12.69 ± 2.77）和（16.81 ± 6.49）μg /mL·h；微粉化片劑相對于原料的相對生物利用度為 132.5 %。大鼠 ig 50 mg/kg T-614 后，尿液中檢測到 T-614 的 5 種主要代謝物，包括 T-614 原結(jié)構(gòu)的異構(gòu)體、苯環(huán)羥基化、脫醛基后再羥基化、脫醛基后胺基乙?；⒚撊┗蟮漠a(chǎn)物。體外CYP450酶活性抑制試驗結(jié)果表明，T-614原料濃度為 20～0.009 1 μmol/L 時，對 CYP2D6、CYP1A2、CYP2C9、CYP2C19 和 CYP3A4 活力抑制的 IC₅₀>20 μmol/L。結(jié)論：大鼠 ig T-614 原料 5、10 和 20 mg/kg 劑量的藥代動力學特征符合一級吸收。在大鼠體內(nèi)各組織中分布較廣，蛋白結(jié)合率低于 30 %。糞、尿、膽汁中原形物質(zhì)的總排泄量低于 20 %。Beagle 犬口服 T-614 片劑的相對生物利用度為 132.5 %。T-614 對人 P450 同工酶 CYP2D6、CYP1A2、CYP2C9、CYP2C19 和 CYP3A4 活力無抑制作用。T-614 在腎臟中代謝轉(zhuǎn)化的主要產(chǎn)物為原形物質(zhì)的異構(gòu)化、羥基化、脫醛基后再羥基化、脫醛基后胺基乙酰化、脫醛基等。

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.