重组人尿激酶原临床I期药代动力学研究

目的: 研究健康受试者单次静脉注射重组人尿激酶原(rhproUK)后的药代动力性质。方法: 采用ELISA分析方法测定血浆总uPA、sc-uPA抗原浓度以及联合免疫生色底物法测定纤溶活性变化。结果: 健康受试者单次静脉注射给药剂量分别为20、40和 60 mg,血浆uPA、sc-uPA和纤溶活性的AUC和C_max呈剂量依赖性增加,剂量比为1∶2∶3,AUC_uPA 之比为 1∶2.1∶3.3;AUC_sc-uPA 之比1 ∶1.9 ∶2.9;不同给药剂量组间的uPA、sc-uPA抗原浓度的CLS、VSS、MRT、末端t_1/2和t_max等参数无统计学差异。血浆纤溶活性浓度时间曲线的AUC和C_max随剂量增加而增加,但表现出一定的非线性变化趋势,C_max之比为1∶2.3∶3.9,AUC之比为1∶2.9∶4.7, CLS与Vd随剂量增加而逐渐减少。结论: 健康受试者个体口服20~60 mg剂量rhproUK后,血浆总u-PA、sc-uPA抗原浓度变化表现为线性药代动力学;而血浆纤溶活性浓度表现出非线性药代动力学特点。

Clinical Phase I Pharmacokinetics of rhproUK

AIM: To investigate pharmacokinetics of rhproUK in healthy subjects. METHODS: ELISA and ELISA combined with chromogenic substrated method were used to determinate the plasma concentration of uPA, sc-uPA and plasminogen activity. RESULTS: The ratio of AUC of uPA and sc-uPA is 1∶2.1 ∶3.3 and 1 ∶1.9 ∶2.9 after single administration of rhproUK in the healthy subjects at the dose of 20,40 and 60 mg per person,AUC and C_max increase with dosage increasment, there are no significant difference in CLS、VSS、MRT、t_1/2 and t_max between three groups.The increasment of AUC and C_max in plasminogen activity are more than the increasment proportion of dosage, the ratio of Cmax and AUC is 1∶2.3∶3.9　and 1∶2.9∶4.7, showed non-linear increasment. CLS and Vd reduce with dosage increasement. CONCLUSION: The course of u-PA, sc-uPA in healthy subjects fitted with the linear pharmacokinetics model in the range from 20 to 60 mg per person, But plasminogen activity showed slightly non-linear pharmacokinetics.