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Pharmacokinetics of Recombinant Human Superoxide Dismutase

Summary: Superoxide dismutase (SOD) disposition was studied in order to design a rational approach for drug administration in the setting of acute myocardial infarction. Four chronically instrumented conscious dogs received the following dosage regimens of recombinant human SOD (rhSOD) on successive days: (a) 5 mg/kg left atrial (LA) bolus, (b) 5 mg/kg central vein (CV) bolus, (c) 15 mg/kg CV bolus, and (d) 5 mg/kg CV infusion over 60 min; additionally, all dogs received (e) a 5 mg/kg CV bolus under pentobarbital anesthesia. Serial serum samples were obtained after each dose and serial myocardial samples were obtained after dose (e). The serum rhSOD concentration was measured by radioimmunoassay and the data were fit to a two-compartment model. The distribution half-life was 7.8 ± 1.7 min (mean ± SEM), and the elimination half-life was 51.1 ± 5.9 min; the central compartment volume of distribution (Vc) was 81 ± 26 ml/kg and the steady-state volume of distribution was 156 ± 20 ml/kg. The dosage regimen had no influence on clearance rates. Peak plasma concentrations (μg/ml) for the dosage regimens were (a) 65 ± 28, (b) 89 ± 19, (c) 214 ± 61, (d) 20 ± 5, and (e) 86 ± 9. The peak level following continuous infusion did not occur until 50 min of infusion and was only one-fourth of the level achieved with a bolus of the same dose. Myocardial levels were <1% of serum levels, suggesting negligible rhSOD penetration into the myocardium. In the setting of an acute myocardial infarction, where the timing of reperfusion may be uncertain, a bolus followed by a continuous infusion may be the ideal means to rapidly achieve and maintain blood levels in order to optimize clinical benefit.