| Abstrakt: |
The pharmacokinetics and thrombolytic properties of a variant of human tissuetype plasminogen activator tPA, obtained by deletion mutagenesis of the NH2terminal fibronectinlike finger F and epidermal growth factor E domains, and substitution of the three known glycosylated Asn residues by Gln tPAFE3X, were studied in dogs with a copper coilinduced thrombosis of the left anterior descending coronary artery. Bolus injections were given during 2 min to groups of three dogs. Injection of 0.15 mgkg resulted in peak antigen levels in plasma of 1.58 ± 0.72 μgml mean ± SEM and caused reperfusion within 14 ± 6 min. With 0.075 mgkg, corresponding values of 0.81 ± 0.20 μgml and 31 ± 15 min were obtained. A bolus of 0.038 mgkg yielded plasma peak levels of 0.43 ± 0.20 μgml but did not cause coronary recanalization within 3 h. A bolus injection of natural tPA MeltPA at a dose of 0.1 mgkg in four dogs resulted in plasma peak levels of 0.46 ± 0.09 μgml and caused partial coronary artery reperfusion within 3 h in one of four dogs after 31 min. None of these injections caused a significant decrease of the fibrinogen level. Pharmacokinetic parameters for tPAFE3X were halflife t½ 1418 min, t½ 72125 min, and plasma clearance 2136 mlmin. For MeltPA, the corresponding values were 3 min, 8 min, and 520 mlmin. We conclude that the variant tPAFE3X has a markedly longer plasma t½ than does MeltPA and, when administered as a bolus injection, a higher thrombolytic efficacy. |
