The pharmacokinetics and thrombolytic properties of a variant of human tissue-type plasminogen activator (t-PA), obtained by deletion mutagenesis of the NH2-terminal fibronectin-like finger (F) and epidermal growth factor (E) domains, and substitution of the three known glycosylated Asn residues by Gln (t-PA-delta FE3X), were studied in dogs with a copper coil-induced thrombosis of the left anterior descending coronary artery. Bolus injections were given during 2 min to groups of three dogs. Injection of 0.15 mg/kg resulted in peak antigen levels in plasma of 1.58 +/- 0.72 micrograms/ml (mean +/- SEM) and caused reperfusion within 14 +/- 6 min. With 0.075 mg/kg, corresponding values of 0.81 +/- 0.20 micrograms/ml and 31 +/- 15 min were obtained. A bolus of 0.038 mg/kg yielded plasma peak levels of 0.43 +/- 0.20 micrograms/ml but did not cause coronary recanalization within 3 h. A bolus injection of natural t-PA (Mel-t-PA) at a dose of 0.1 mg/kg in four dogs resulted in plasma peak levels of 0.46 +/- 0.09 micrograms/ml 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 t-PA-delta FE3X were alpha half-life (t1/2) 14-18 min, beta t1/2 72-125 min, and plasma clearance 21-36 ml/min. For Mel-t-PA, the corresponding values were 3 min, 8 min, and 520 ml/min. We conclude that the variant t-PA-delta FE3X has a markedly longer plasma t1/2 than does Mel-t-PA and, when administered as a bolus injection, a higher thrombolytic efficacy.