单链尿激酶型纤溶酶原激活剂在兔及猕猴中的生物转化和药代动力学

目的：研究重组单链尿激酶型纤溶酶原激活剂(rh-sc-uPA)单链和代谢物双链(tc-uPA)的药代动力学和转化。方法：¹²⁵I标记结合生化反应及RP-HPLC测定血浆¹²⁵I-sc-uPA和¹²⁵I-tc-uPA浓度；平板溶圈法测定血浆溶纤组分浓度。结果：兔iv ¹²⁵I-sc-uPA后单链呈双指数消除，T_1/2α和T_1/2β分别为7和43 min，双链呈单指数消除T_1/2=9 min，约有38%单链转化为双链。猕猴静脉推注不同剂量rh-sc-uPA后血浆纤溶组分浓度呈单指数下降，T1/2分别为(6.3±1.8) min, (11.5±2.1) min和(12.3±2.9) min，CLS随剂量变慢。推注n-tc-uPA T_1/2=(13.7±2.7) min。结论：兔iv ¹²⁵I-sc-uPA后可检测到¹²⁵I-rh-sc-uPA与¹²⁵I-tc-uPA。猕猴iv rh-sc-uPA后血浆溶纤组分浓度呈非线性变化。

BIO-TRANSFORMATION AND PHARMACOKINETICS OF SINGLE CHAIN UROKINASE-TYPE PLASMINOGEN ACTIVATOR IN RABBITS AND RHESUS MONKEYS

AIM: The concentration profiles of recombinant human single chain urokinase-type plasminogen activator (rh-sc-uPA) and bio-transformation to two-chain metabolite (tc-uPA) were studied after iv bolus injection of ¹²⁵I-rh-sc-uPA in rabbits. Fibrinolytic components-time curves in plasma were determined after iv bolus injection at different doses of rh-sc-uPA in rhesus monkeys and were compared with natural urokinase (n-tc-uPA). METHODS: Aprotinin was added into plasma immediately after sampling for preventing the conversion of single-chain to two-chain. Plasma ¹²⁵I-sc-uPA concentrations was determined by RP-HPLC of dithiothreitol (DTT) treated plasma, while concentrations of ¹²⁵I-sc-uPA+¹²⁵I-tc-uPA was obtained by analysis of untreated DTT plasma. Concentration of fibrinolytic components was assayed by fibrin plate method in vitro. RESULTS: The ¹²⁵I-sc-uPA and ¹²⁵I-tc-uPA were both detected after iv bolus injection of in rabbits. The ¹²⁵I-sc-uPA concentrations were best fit by a two-compartment model with T_1/2α and T_1/2β equaled to 7 and 43 min, respectively. ¹²⁵I-tc-uPA concentrations were best fit by a one-compartment model with elimination T_1/2　of 9 min. Nearly 38% of ¹²⁵I-sc-uPA transformed to ¹²⁵I-tc-uPA. Concentration of fibrinolytic components decreased rapidly after iv bolus injection of 7.5×10⁴, 1.5×10⁵, and 3.0×10⁵ U.kg^-1 rh-sc-uPA in rhesus Monkeys. Elimination T_1/2　were 6.3±1.8, 11.5±2.1 and 12.3±2.9 min, respectively (P<0.05～P<0.01). Systemic clearance were 0.051±0.030, 0.022±0.006 and 0.016±0.003 L.min^-1.kg^-1, respectively (P<0.05). Concentration of fibrinolytic components after 1.5×105 U.kg^-1 of rh-sc-uPA was significantly lower than that after n-tc-uPA. CONCLUSION: ¹²⁵I-rh-sc-uPA and its active metabolite-¹²⁵I-rh-tc-uPA were detected after iv of ¹²⁵I-rh-sc-uPA in rabbits, their pharmacokinetic behaviors were different. Deposition profiles of fibrinolytic components after iv of various doses of rh-sc-uPA in monkeys follows non-linear pharmcokinetics.