Non-linear kinetics of 4-methylpyrazole in healthy human subjects

In order to evaluate the pharmacokinetic profile of the alcohol dehydrogenase inhibitor 4-methylpyrazole 4-MP, a placebo-controlled, double-blind, single-dose, randomized, sequential, ascending-dose "Phase-I study" was performed in healthy male volunteers at dose levels of 10 (n = 4), 20 (n = 4), 50 (n = 4) and 100 mg.kg-1 (n = 3). In the 10 and 20 mg.kg-1 group, the elimination of 4-MP from the plasma followed non-linear kinetics with mean rates of concentration decline of 3.66 and 5.05 mumol.l-1.h-1, respectively. In the two highest dose groups, the elimination also appeared to be non-linear although the patterns were not followed long enough to confirm this. The mean rates of concentration decline at the higher doses were significantly increased, up to 14.9 mumol.l-1.h-1 at 100 mg.kg-1. The average renal clearance of 4-MP was low, 0.016 ml.min-1.kg-1, and only 3% of the administered dose was excreted unchanged in the urine, indicating metabolism as the major route of elimination. Because of the apparently unusual kinetics following single dose treatment, thorough multiple dose studies need to be carried out to determine a safe dosage regimen for 4-MP.