The pharmacokinetics and effects of a long-acting preparation of superoxide dismutase (PC-SOD) in man.
OBJECTIVE
To study the pharmacokinetics (PK), safety and tolerability of single rising doses up to 80 mg of superoxide dismutase covalently linked to lecithin (PC-SOD) in healthy White volunteers.


METHODS
This double-blind, placebo-controlled, four-period cross-over study was performed in eight healthy volunteers (four male/four female). Three doses of PC-SOD (20, 40 and 80 mg) and placebo were administered intravenously in randomized order. Serum and urinary PC-SOD concentrations were measured predose and up to 96 h after dosing. In addition to standard safety measurements, the urinary excretion of N-acetyl-beta-glucosaminidase, alpha-glutathione S-transferase (alpha-GST) and pi-GST was measured to evaluate renal function. The PK of PC-SOD was analysed using noncompartmental and compartmental methods.


RESULTS
All treatments were well tolerated, and no obvious relationship between adverse events and treatment was observed. No effects of PC-SOD on renal function could be detected. Dose normalized C(max) and AUC were not different between the different dosages, indicating linearity of plasma concentrations with dose. Estimated PC-SOD clearance was 2.54 ml min(-1)[95% confidence interval (CI) 2.07, 2.83]. The terminal half-life was estimated to be 1.54 days (95% CI 0.93, 2.15). SOD activity was elevated above baseline for 19 +/- 6 h after the 80-mg dose.


CONCLUSIONS
Single intravenous administrations of PC-SOD in doses up to 80 mg were well tolerated in healthy White male and female volunteers. With the doses used, SOD activity was linearly related to the dose; after the 80-mg dose it was present for an appreciable period. These findings suggest that it is worthwhile to investigate PC-SOD in clinical conditions characterized by a high radical overload.
Broeyer
F J F
FJ
Centre for Human Drug Research, Leiden, The Netherlands.
van Aken
B E
BE
Suzuki
J
J
Kemme
M J B
MJ
Schoemaker
H C
HC
Cohen
A F
AF
Mizushima
Y
Y
Burggraaf
J
J
D000293:Adolescent; D000328:Adult; D019540:Area Under Curve; D003692:Delayed-Action Preparations / Q000493:pharmacokinetics / Q000494:pharmacology; D004311:Double-Blind Method; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000494:pharmacology
D003692:Delayed-Action Preparations; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase