Distribution of oral 4-methylpyrazole in the rat: Inhibition of elimination by ethanol

Abstract

4-Methylpyrazole (4-MP), a potent competitive inhibitor of alcohol dehydrogenase activity, is being studied as a therapeutic agent for methanol and ethylene glycol poisoning. In order to evaluate the distribution of 4-MP using doses in the potentially therapeutic range, male Sprague-Dawley rats were administered 4-MP orally at zero time in doses of 5, 10, or 20 mg/kg. Half of the rats were also treated orally at 0, 1, 2, and 3 h with ethanol (1 g/kg each h) and half with glucose in isocaloric amounts. At doses of 10 and 20 mg/kg, 4-MP elimination appeared to be saturated, with an elimination rate of 10 μmol/L/h. Elimination at 5 mg/kg was non-conclusive as to the order. The rate of 4-MP elimination was decreased about 50% by concomitant administration of ethanol. Urinary excretion of unchanged 4-MP accounted for only about 1% of the dose; the amount excreted unchanged was significantly increased by ethanol administration. The results demonstrate the mutual inhibition of metabolism by ethanol and 4-methylpyrazole, which may explain why the inhibition of ADH by 4-MP can be longer than that predicted by the elimination rate of 4-MP alone.