The safety and pharmacokinetics of MCI-186 (edaravone, 3-methyl-1-phenyl-2-pyrazolin-5-one), a novel agent for cerebrovascular disease, were investigated in healthymale volunteers following a single intravenous infusion at doses of 0.2, 0.5, 1 .0, 1.5 and 2.0mg/kg and after 7 days of repeated administration at a dose of 1.0 mg/kg per day. Eachstep was studied in 7 volunteers (active drug: 5, placebo: 2).
In clinical laboratory tests, the increases of serum total bilirubin at a dose of 0.2 mg/kg and placebo in one each, and a decrease of serum platelet count at a dose of 0.5 mg/kg were observed. No other apparent changes were observed in any subject. MCI-186 hada good tolerability profile in healthy volunteers.
The plasma concentrations after a single intravenous infusion for 40 min (0.2-1 .5mg/kg) reached maximum levels (222.53-3060.73ng/ml) at 40min after the beginningof infusion, and then decreased rapidly with half-lives of 0.15-0.17 hr (t1/2α) and 1.45 hr (t1/2β) at doses of 0.2mg/kg and 0.5mg/kg, and 0.17 hr (t1/2α), 0.81-0.85 hr (t1/2β) and4.50-5.16 hr (t1/2γ) at doses of 1.0mg/kg and 1.5mg/kg. The Cmax and AUC increasedproportionally to doses from 0.2mg/kg to 1.5mg/kg.
The plasma concentrations after a single intravenous infusion for 3 hr reached amaximum level (1225.96 ng/ml) at 3 hr after the beginning of infusion, and then decreasedrapidly with half-lives of 0.12 hr (t1/2α), 0.65 hr (t1/2β) and 4.38 hr (t1/2γ) at adose of 2.0 mg/kg. These plasma concentrations corresponded to those calculated fromthe pharmacokinetic parameters obtained by the analysis of plasma concentrations aftera single intravenous infusion for 40 min at a dose of 1.5 mg/kg.
The plasma concentrations after repeated intravenous infusions for 40 min reachedmaximum levels (1616.21-1819.13 ng/ml) 40 min after the beginning of infusion, andthen decreased rapidly in a similar manner with a single intravenous infusion for 40 min.
MCI-186 was metabolized and excreted rapidly in urine within 24hr after thebeginning of infusion. Urinary excretion rates of MCI-186, sulfate and glucuronide were0.56-0.98%, 5.61-13.16% and 68.64-83.17% of the dose, respectively. Irrespective of thedose and infusion time, urinary excretion rates of MCI-186 and its conjugates werealmost the same.
