Abstract

The absorption, distribution, excretion, and metabolism of 14C-nafimidone, a novel anticonvulsant, have been studied in rats. Nafimidone was completely absorbed following single oral doses of 10 and 100 mg/kg. After both iv and oral administration, nafimidone was rapidly eliminated from plasma (t 1/2 about 5 min), with concomitant formation of a pharmacologically active, nonconjugated metabolite, nafimidone alcohol. Systemic clearance of nafimidone from plasma after iv administration was approximately 2 times higher than hepatic blood flow in rats, and the oral bioavailability was 15%. However, the AUC of nafimidone alcohol was 30% higher after oral administration of nafimidone than that after iv administration of nafimidone. It is likely that, given its pharmacological activity, nafimidone alcohol is the more important species pharmacologically. Distribution of nafimidone-related radioactivity was widespread with highest concentrations associated with liver, kidney, adrenals, and the gastrointestinal tract. Elimination of radioactivity from tissues was rapid and complete, except that retention was noted in arterial vessels and in the ocular melanin of pigmented rats. Determination of hepatic and brain levels of nafimidone and nafimidone alcohol showed no detectable levels of nafimidone in either tissue. However, levels of nafimidone alcohol in liver and brain were as much as 13-fold and 2-fold, respectively, higher than levels in plasma. After either iv or oral administration of 14C-nafimidone, approximately two-thirds of the radioactivity was recovered in urine. The major urinary metabolites of nafimidone after a 100 mg/kg dose were characterized and shown to be dihydroxydihydronaphthalene, substituted nafimidone alcohol, and the 1-beta-glucuronide of nafimidone alcohol.