PHARMACOKINETICS AND CORONARY THROMBOLYTIC PROPERTIES OF 2 HUMAN TISSUE-TYPE PLASMINOGEN-ACTIVATOR VARIANTS LACKING THE FINGER-LIKE, GROWTH FACTOR-LIKE, AND 1ST KRINGLE DOMAINS (AMINO-ACIDS 6-173) IN A CANINE MODEL

The pharmacokinetics and thrombolytic properties of two variants of recombinant human tissue-type plasminogen activator (rt-PA) were studied in dogs with a copper coil induced thrombosis of the left anterior descending coronary artery. The first variant, rt-PA-ΔFEK1-Gln184, lacked amino acids 6 to 173 [comprising the fibronectin finger-like (F), the epidermal growth factor-like (E), and the first kringle (K1) domains] and had the glycosylated Asn184 mutagenized to Gln. The second variant, rt-PA-ΔFEK1-Gln184, Val277, had in addition Lys277 mutagenized to Val. Injection of 0.25, 0.50, or 1.0 mg/kg of rt-PA in groups of three dogs caused reflow in six of nine dogs, within 18 ± 15 min (mean ± SD), but was associated with reocclusion within 2 h in all animals. Injection of 0.125, 0.25, or 0.50 mg/kg of rt-PA-ΔFEK1-Gln184 caused reflow in all of nine dogs, within 17 ± 23 min, with persistent patency in four animals (p = 0.02 vs. rt-PA). Bolus injection of 4:1 mixtures of rt-PA-ΔFEK1-Gln184 and rt-PA in total amounts of 0.125, 0.25, or 0.50 mg/kg resulted in reflow in eight of nine dogs within 25 ± 21 min with persistent patency in seven (p = 0.003 vs. rt-PA, p = 0.25 vs. rt-PA-ΔFEK1-Gln184 alone). Injection of 0.25, 0.50, or 1.0 mg/kg of rt-PA-ΔFEK1-Gln184, Val277 produced reperfusion in six of nine dogs, within 27 ± 26 min, with persistent patency in three (p = 0.59 vs. rt-PA and p = 0.23 vs. rt-PA-ΔFEK1-Gln184). Fibrinogen breakdown was negligible with rt-PA, moderate (30 to 60%) with rt-PA-ΔFEK1-Gln184, and extensive (>90%) with rt-PA-ΔFEK1-Gln184, Val277. Plasma clearance was 27-39 ml/min for rt-PA-ΔFEK1-Gln184; 16-32 ml/min for rt-PA-ΔFEK1-Gln184, Val277; and 320-540 ml/min for rt-PA. © 1990 Raven Press, Ltd., New York.