氚标记小牛胸腺DNA在大鼠和犬体内的药动学研究

Pharmacokinetics Study of Tritium-labeled Calf Thymus DNA in Rats and Dogs

目的:研究氚标记小牛胸腺DNA(3H-小牛胸腺DNA)在大鼠和Beagle犬体内的药动学特征。方法:采用氚水交换法制备3H-小牛胸腺DNA。取大鼠尾静脉注射高、中、低剂量(15、5、1.67 mg/kg,n=5)的3H-小牛胸腺DNA,中、高剂量组大鼠连续给药7d(第1、7天给予3H-小牛胸腺DNA,其余时间给予未标记小牛胸腺DNA),低剂量大鼠仅单次给药;另取犬前肢静脉注射高、中、低剂量(1.5、0.5、0.167 mg/kg,n=3)的3H-小牛胸腺DNA,中剂量犬连续给药7 d,低、高剂量犬仅单次给药。分别于第1、7天给药后0.033、0.25、1、2、4、6、8、12、24 h取血,分离血浆后加入闪烁液并使用液闪计数仪分析,以WinNonlin软件计算药动学参数。结果:高、中、低剂量3H-小牛胸腺DNA在大鼠体内的药动学参数分别为:单次给药的AUC0-24 h为(11 742±2 245)、(3 571±851)、(727±202)ng-Eq·h/g,t1/2为(21.4±5.08)、(13±6.0)、(6.8±1.76)h;重复给药高、中剂量的AUC0-24 h为(5 706±1 009)、(7 601±1 861)ng-Eq·h/g,t1/2为(16.0±10.13)、(9±2.7)h。高、中、低剂量3H-小牛胸腺DNA在犬体内的药动学参数分别为:单次给药的AUC0-24 h为(4 444±999)、(2 719±139)、(501±101)ng-Eq·h/g,t1/2为(17.6±7.57)、(14.0±1.76)、(16.4±2.39)h;重复给药中剂量的AUC0-24 h为(3 073±200)ng-Eq·h/g,t1/2为(20.6±6.62)h。结论:3H-小牛胸腺DNA在大鼠与Beagle犬体内单次给药和重复给药均可被快速消除。

OBJECTIVE： To study the pharmacokinetic characteristics of tritium-labeled calf thymus DNA （3H-ctDNA） in rats and Beagle dogs. METHODS： Isotope exchange method was used to synthesize 3H-ctDNA. The rats were given high-dose, medi- um-dose and low-dose of 3H-ctDNA via tail vein injection （15, 5, 1.67 mg/kg, n=5）; high-dose and medium-close groups were given 3H-ctDNA for consecutive 7 days （injecting with 3H-ctDNA on first and seventh day and non-labeled calf thymus DNA on oth- er days） while low-dose group was given ~H-ctDNA just once. Dogs were given high-dose, medium-dose and low-dose of ~H-ctD- NA via forelimb vein （1.5, 0.5, 0.167 mg/kg,n=3） ; medium-dose group was given 3H-ctDNA for consecutive 7 days while other two groups were given 3H-ctDNA just once. The blood samples were collected 0.033 h, 0.25 h, 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h after medication on first and seventh day, respectively. Scintillation solution was added into samples after separating plasma, and then analyzed with scintillation count. The pharmacokinetic parameters were estimated by using WinNonlin software. RE- SULTS： Pharmacokinetic parameters of high-dose, medium-dose and low-dose of 3H-ctDNA in rats were as follows： in single dose, AUC0-24h were （11 742 ± 2 245） ng-Eq-h/g, （3 571 ± 851） ng-Eq-h/g and （727 ± 202） ng-Eq-h/g, tt/2 were （21.4± 5.08） h, （13 ± 6.0） h and （6.8 ± 1.76） h; in multiple dose, AUC0 24 h of high-dose and medium-dose were （5 706 ± 1 009） ng-Eq, h/g and （7 601 ± 1 861） ng-Eq.h/g, t1/2 were（16.0 _± 10.13） h and （9 ± 2.7） h. Pharmacokinetic parameters of high-dose, medium-dose and low-dose of 3H-ctDNA in Beagle dogs were as follows： in single dose, AUC0-24h were （4 444 ± 999） ng-Eq.h/g, （2 719 ± 139） ng-Eq.h/g and （501 _± 101） ng-Eq-h/g, tt/2 were （17.6 ± 7.57） h, （14.0± 1.76） h and （16.4±2.39） h; in multiple dose, AUC0-24h of medium-dose were （3 073 ± 200） ng-Eq.h/g, tl/2 were （20.6 ± 6.62） h. CONCLUSIONS： Single dose and multiple doses of 3H-ctD- NA are rapidly eliminated in rats and Beagle dogs.