金黄色葡萄糖球菌肠毒素C2改构蛋白大鼠药动学研究

目的 研究金黄色葡萄糖球菌肠毒素C2改构蛋白（2M-118）在大鼠体内单次和多次给药后的药动学特征。方法 24只大鼠随机分为3组，每组8只，雌雄各半，分别单次iv低、中和高剂量（1、2和4 mg/kg）2M-118，高剂量组大鼠于单次给药后，继续每天给药1次，共给药8次。于给药前（0 h），首次及末次给药后5、10、20、30、45 min和1.0、1.5、2.0、4.0、6.0、8.0 h采集眼静脉丛全血约0.5 mL，制备血清。采用双抗体夹心酶联免疫吸附测定（ELISA）法检测大鼠血清药物浓度，采用DAS 3.2.8药动程序计算药动学参数。结果 大鼠单次iv 2M-118后，在1～4 mg/kg剂量内，峰浓度（C_max）、初始浓度（C₀）和药时曲线下面积（AUC）均与剂量呈正相关；消除相半衰期（t_1/2Z）随剂量递增明显延后，平均t_1/2z分别为0.24、0.60和1.18 h；表观分布容积（V_z）随剂量递增而增大；各剂量组的清除率（CL_z）较为一致。与同剂量（4 mg/kg）单次给药相比，大鼠多次给药后的主要药动学参数基本保持一致，体内药物无蓄积倾向。结论 大鼠单次iv 2M-118后，在1～4 mg/kg剂量内，体内暴露量与剂量呈正相关，其清除可能呈现非线性动力学特征；单次与多次iv给予相同剂量2M-118后，药动学行为特征基本一致，无明显药物蓄积。

Pharmacokinetics of a mutated staphylococcal enterotoxin C2 in rat

Objective To investigate the pharmacokinetic profiles of a mutated staphylococcus enterotoxin C2, named 2M-118, after single and multiple intravenous administration in rat. Methods 24 rats were randomly divided into three groups, including low-dose (1 mg/kg), medium-dose (2 mg/kg) and high-dose (4 mg/kg) groups of 2M-118. Each group included 8 rats, with male and female animals each half. All animals were intravenously administrated at a single dose, after that the rats in high-dose group were continuously dosed once a day for another 7 times. Before administration (0 h), 5, 10, 20, 30, 45 min (0.083, 0.170, 0.750, 0.330, 0.500, 0.750 h), 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 h after the first and last administration, 0.5 ml of whole blood was collected to prepare serum. An ELISA method was developed to determine the dynamic changes of drug concentration in serum, and pharmacokinetic parameters were calculated by using DAS 3.2.8 pharmacokinetics program. Results Pharmacokinetic parameters in rat between different single dose groups were as follows:the peak concentration C_max, initial concentration C₀, and area under the drug curve AUC were all positively related with increasing dose. The elimination phase half-life t_1/2Z was significantly delayed with increasing dose. The mean values of t_1/2z were 0.24, 0.60 and 1.18 h, respectively. The apparent distribution volume V_z tended to increase with the increasing dose. The values of clearance rate CL_z were consistent between groups. Compared with the single dose (4 mg/kg), the main PK parameters were basically consistent after multiple same doses, indicating that there was no tendency of drug accumulation after repeatedly intravenous administration of 2M-118 in rats. Conclusion After a single intravenously dose of 2M-118 in rats, drug exposure in vivo was positively correlated with dose in the range of 1-4 mg/kg, and its clearance possibly presented non-linear dynamic characteristics.The characteristics of pharmacokinetics were basically consistent between single and multiple dose of 4 mg/ kg 2M-118, and there was no significant drug accumulation observed.