z目的 評價鹽酸左氧氟沙星注射液在Beagle犬體內(nèi)的暴露情況及其對動物的長期毒性研究。方法 建立Beagle犬血漿樣品中左氧氟沙星的高效液相色譜（HPLC）檢測方法；Beagle犬按分層隨機(jī)法分為對照組和鹽酸左氧氟沙星注射液低、高劑量（20、40 mg/kg，分別為人臨床擬用劑量的2.33、4.67倍）組，每組8只。iv給藥，對照組iv生理鹽水，1次/d，給藥期4周，恢復(fù)期4周。對Beagle犬首、末次給藥后血漿樣品進(jìn)行分析測定，采用Winnolin 6.2.1采用非房室模型法（NCA）判定鹽酸左氧氟沙星注射液對受試動物體內(nèi)毒動學(xué)的影響。觀察動物一般狀態(tài)；采用生物機(jī)能實(shí)驗(yàn)系統(tǒng)，以II導(dǎo)聯(lián)記錄Beagle犬給藥前、給藥期結(jié)束、恢復(fù)期結(jié)束Beagle犬在清醒狀態(tài)下的心電圖。結(jié)果 首次給藥后，雄性Beagle犬低、高劑量組C_max、AUC_0-t比值分別為1：1.86和1：2.19，MRT比值為1：1.16，CL_F比值為1：0.77，t_1/2比值為1：1.44；末次給藥后，低、高劑量組C_max、AUC_0-t比值分別為1：3.73和1：2.24，MRT比值為1：0.87，CL_F比值為1：0.92，t_1/2比值為1：0.94。首次給藥后，雌性Beagle犬低、高劑量組C_max、AUC_0-t比值分別為1：2.10和1：2.12，MRT比值為1：1.02，CL_F比值為1：0.63，t_1/2比值為1：1.05；末次給藥后，低、高劑量組C_max、AUC_0-t比值分別為1：1.88和1：1.53，MRT比值為1：0.67，CL_F比值為1：1.47，t_1/2比值為1：0.66。鹽酸左氧氟沙星注射液低劑量組動物給藥第1周內(nèi)出現(xiàn)困倦（2/8），皮膚水腫、發(fā)紅（2/8），上瞼松弛（1/8），唾液分泌過多（1/8），嘔吐（1/8）；給藥第2~4周出現(xiàn)皮膚水腫（1/8）、發(fā)紅（1/8）；恢復(fù)期癥狀消失；高劑量組動物給藥第1、2天出現(xiàn)上瞼松弛（1/8），部分動物出現(xiàn)短期或長期的皮膚水腫（4/8）、困倦（5/8）、嘔吐或干嘔（6/8）、唾液分泌過多（7/8）、鼻有分泌物（2/8）、皮膚發(fā)紅（2/8）；給藥第2、3周開始出現(xiàn)肌張力降低（2/8），偶爾出現(xiàn)大小便失禁（4/8）；恢復(fù)期癥狀消失。給藥前各組心電指標(biāo)無明顯差異。給藥結(jié)束鹽酸左氧氟沙星注射液低、高劑量組心率顯著高于對照組（P<0.05、0.01），低、高劑量組PR間期顯著低于對照組（P<0.05、0.01）；高劑量組QT間期顯著低于對照組（P<0.05）；恢復(fù)期結(jié)束高劑量組心率顯著高于對照組（P<0.05），且作用均呈劑量相關(guān)性。結(jié)論 不同劑量的鹽酸左氧氟沙星注射液在Beagle犬體內(nèi)存在暴露和蓄積差異；高劑量組雌性Beagle犬藥物代謝加快，可能誘導(dǎo)了肝藥酶活性，致使藥物在體內(nèi)的暴露減少；供試品高于臨床等效劑量給藥在給藥期間可能發(fā)生過敏反應(yīng)、消化系統(tǒng)損害、全身性損害、神經(jīng)系統(tǒng)毒性和心血管系統(tǒng)損害，恢復(fù)期癥狀消失。

Objective To analyze and determine plasma samples of Levofloxacin Hydrochloride Injection administered iv around Beagle dogs in order to evaluate its exposure in Beagle dogs and to provide reference for clinical studies on the toxicity of the donor to animals. Method An HPLC method was established for the determination of levofloxacin in plasma samples of Beagle dogs. Beagle dogs were randomly divided into control group and levofloxacin hydrochloride injection low and high dose (20 and 40 mg/kg, respectively, 2.33 and 4.67 times of human clinical dose) groups, with eight dogs in each group. The control group was given normal saline, once a day, seven days a week. The administration period was four weeks and the recovery period was four weeks. Plasma samples were analyzed and measured after the first and last iv injections of levofloxacin hydrochloride injection in Beagle dogs, and Winnolin 6.2.1 was used to determine the effect of levofloxacin hydrochloride injection on the body of the test animals using the non-compartmental model (NCA) method. The general state of the animals was observed, and the ECG of beagle dogs in awake state was recorded with lead II before administration, at the beging and end of administration period and at the end of recovery period. Results After the first administration, the C_max and C_max ratios of male Beagle dogs in the low and medium dose groups were 1:1.86 and 1:2.19 respectively, the MRT ratios was 1:1.16, the CL_F ratio was 1:0.77, The t_1/2 ratio was 1:1.44; After the last administration, the C_max and C_max ratio of low and medium dose groups were 1:3.73 and 1:2.24 respectively. the MRT ratio was 1:0.87, the CL_F ratio was 1:0.92, the t_1/2 ratio was 1:0.94; After the first administration, the C_max and C_max ratios of female Beagle dogs were 1:2.10 and 1:2.12, respectively between the low and medium dose group. The MRT ratio was 1:1.02, the ratio of CL_F was 1:0.63, the t_1/2 ratio was 1:1.05; After the last administration, the C_max and C_max ratios of low and medium dose groups were 1:1.88 and 1:1.53 respectively. The MRT ratio was 1:0.67, the CL_F ratio was 1:1.47, the t_1/2 ratio was 1:0.66. Drowsiness (2/8), Skin edema and redness (2/8), upper eyelid relaxation (1/8), saliva secretion excessive (1/8), vomiting (1/8) occurred in the low-dose group of levofloxacin hydrochloride injection within the first week. Skin edema (1/8) and red (1/8) occurred in the low-dose group in 2-4 week. The symptoms disappeared in the recovery period. In the high-dose group, upper eyelid relaxation occurred on the first and second day (1/8). Some animals developed short-term or long-term skin edema (4/8), drowsiness (5/8), vomiting or retching (6/8), salivary hypersecretion (7/8), nasal secretion (2/8), and red skin (2/8); At the second and third week of administration, the muscle tone began to decrease (2/8), occasionally incontinence (4/8); The symptoms disappeared in the recovery period. There was no significant difference in ECG before administration. At the end of administration, the heart rate of low-dose and high-dose levofloxacin hydrochloride injection groups was significantly higher than that of control group (P<0.05 or 0.01). The PR interval of low and high dose groups was significantly lower than that of control group (P<0.05 or 0.01), QT interval of high dose group was significantly lower than that of control group (P<0.05). At the end of the recovery period, the heart rate of the high-dose group was significantly higher than that of the control group (P<0.05). The effects were dose-dependent. Conclusion There are differences in exposure and accumulation of levofloxacin hydrochloride injection in beagle dogs at different doses; the drug metabolism of female beagle dogs in the middle dose group is accelerated, which may induce the activity of liver drug enzymes. The exposure of the drug in the body is reduced. The test product may have allergic reactions, digestive system damage, systemic damage, nervous system toxicity and cardiovascular system damage during the administration period when the dose higher than clinical equivalent dose. Symptoms disappear during convalescence.

R969.1

國家自然科學(xué)基金（81803995，82004243）；黑龍江省博士后資助（LBH-Z16196）；黑龍江中醫(yī)藥大學(xué)博士創(chuàng)新科研基金項(xiàng)目（051761）；黑龍江省中醫(yī)藥學(xué)會青年科技創(chuàng)新基金（ZHY19-013）；黑龍江省自然科學(xué)基金（LH2020H081）