目的 研究金黃色葡萄糖球菌腸毒素C2改構蛋白（2M-118）在大鼠體內(nèi)單次和多次給藥后的藥動學特征。方法 24只大鼠隨機分為3組，每組8只，雌雄各半，分別單次iv低、中和高劑量（1、2和4 mg/kg）2M-118，高劑量組大鼠于單次給藥后，繼續(xù)每天給藥1次，共給藥8次。于給藥前（0 h），首次及末次給藥后5、10、20、30、45 min和1.0、1.5、2.0、4.0、6.0、8.0 h采集眼靜脈叢全血約0.5 mL，制備血清。采用雙抗體夾心酶聯(lián)免疫吸附測定（ELISA）法檢測大鼠血清藥物濃度，采用DAS 3.2.8藥動程序計算藥動學參數(shù)。結(jié)果 大鼠單次iv 2M-118后，在1～4 mg/kg劑量內(nèi)，峰濃度（C_max）、初始濃度（C₀）和藥時曲線下面積（AUC）均與劑量呈正相關；消除相半衰期（t_1/2Z）隨劑量遞增明顯延后，平均t_1/2z分別為0.24、0.60和1.18 h；表觀分布容積（V_z）隨劑量遞增而增大；各劑量組的清除率（CL_z）較為一致。與同劑量（4 mg/kg）單次給藥相比，大鼠多次給藥后的主要藥動學參數(shù)基本保持一致，體內(nèi)藥物無蓄積傾向。結(jié)論 大鼠單次iv 2M-118后，在1～4 mg/kg劑量內(nèi)，體內(nèi)暴露量與劑量呈正相關，其清除可能呈現(xiàn)非線性動力學特征；單次與多次iv給予相同劑量2M-118后，藥動學行為特征基本一致，無明顯藥物蓄積。

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.

R969.1

“十二五”國家重大新藥創(chuàng)制項目（2012ZX09102301-013）