Premium
The pharmacokinetics and effects of a long‐acting preparation of superoxide dismutase (PC‐SOD) in man
Author(s) -
Broeyer F. J. F.,
Van Aken B. E.,
Suzuki J.,
Kemme M. J. B.,
Schoemaker H. C.,
Cohen A. F.,
Mizushima Y.,
Burggraaf J.
Publication year - 2008
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2007.02965.x
Subject(s) - pharmacokinetics , tolerability , placebo , superoxide dismutase , pharmacology , dose , medicine , adverse effect , urinary system , excretion , chemistry , oxidative stress , pathology , alternative medicine
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Reactive oxygen species (ROS), like superoxide anion, play an important role in different disease states. • Superoxide dismutase (SOD) acts as a free radical scavenger by catalysing the dismutation of superoxide. • Over the last decade, therapeutic use of SOD has been explored, but the results of these experiments have indicated that this has been of limited value, probably due to unfavourable pharmaceutical characteristics of the compounds. WHAT THIS STUDY ADDS • Single intravenous administrations of PC‐SOD (SOD covalently linked to lecithin) in doses up to 80 mg was well tolerated and biologically active for a period of 19 ± 6 h in healthy White volunteers. • This suggests that PC‐SOD has pharmaceutically appropriate characteristics and may be a possible protective agent for patients in clinical conditions characterized by acute high radical overload. AIM 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‐β‐glucosaminidase, α‐glutathione S‐transferase (α‐GST) and π‐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.