z目的 评价盐酸左氧氟沙星注射液在Beagle犬体内的暴露情况及其对动物的长期毒性研究。方法 建立Beagle犬血浆样品中左氧氟沙星的高效液相色谱（HPLC）检测方法；Beagle犬按分层随机法分为对照组和盐酸左氧氟沙星注射液低、高剂量（20、40 mg/kg，分别为人临床拟用剂量的2.33、4.67倍）组，每组8只。iv给药，对照组iv生理盐水，1次/d，给药期4周，恢复期4周。对Beagle犬首、末次给药后血浆样品进行分析测定，采用Winnolin 6.2.1采用非房室模型法（NCA）判定盐酸左氧氟沙星注射液对受试动物体内毒动学的影响。观察动物一般状态；采用生物机能实验系统，以II导联记录Beagle犬给药前、给药期结束、恢复期结束Beagle犬在清醒状态下的心电图。结果 首次给药后，雄性Beagle犬低、高剂量组C_max、AUC_0-t比值分别为1：1.86和1：2.19，MRT比值为1：1.16，CL_F比值为1：0.77，t_1/2比值为1：1.44；末次给药后，低、高剂量组C_max、AUC_0-t比值分别为1：3.73和1：2.24，MRT比值为1：0.87，CL_F比值为1：0.92，t_1/2比值为1：0.94。首次给药后，雌性Beagle犬低、高剂量组C_max、AUC_0-t比值分别为1：2.10和1：2.12，MRT比值为1：1.02，CL_F比值为1：0.63，t_1/2比值为1：1.05；末次给药后，低、高剂量组C_max、AUC_0-t比值分别为1：1.88和1：1.53，MRT比值为1：0.67，CL_F比值为1：1.47，t_1/2比值为1：0.66。盐酸左氧氟沙星注射液低剂量组动物给药第1周内出现困倦（2/8），皮肤水肿、发红（2/8），上睑松弛（1/8），唾液分泌过多（1/8），呕吐（1/8）；给药第2~4周出现皮肤水肿（1/8）、发红（1/8）；恢复期症状消失；高剂量组动物给药第1、2天出现上睑松弛（1/8），部分动物出现短期或长期的皮肤水肿（4/8）、困倦（5/8）、呕吐或干呕（6/8）、唾液分泌过多（7/8）、鼻有分泌物（2/8）、皮肤发红（2/8）；给药第2、3周开始出现肌张力降低（2/8），偶尔出现大小便失禁（4/8）；恢复期症状消失。给药前各组心电指标无明显差异。给药结束盐酸左氧氟沙星注射液低、高剂量组心率显著高于对照组（P<0.05、0.01），低、高剂量组PR间期显著低于对照组（P<0.05、0.01）；高剂量组QT间期显著低于对照组（P<0.05）；恢复期结束高剂量组心率显著高于对照组（P<0.05），且作用均呈剂量相关性。结论 不同剂量的盐酸左氧氟沙星注射液在Beagle犬体内存在暴露和蓄积差异；高剂量组雌性Beagle犬药物代谢加快，可能诱导了肝药酶活性，致使药物在体内的暴露减少；供试品高于临床等效剂量给药在给药期间可能发生过敏反应、消化系统损害、全身性损害、神经系统毒性和心血管系统损害，恢复期症状消失。

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

国家自然科学基金（81803995，82004243）；黑龙江省博士后资助（LBH-Z16196）；黑龙江中医药大学博士创新科研基金项目（051761）；黑龙江省中医药学会青年科技创新基金（ZHY19-013）；黑龙江省自然科学基金（LH2020H081）