TOXICOKINETICS OF 4-METHYLIMIDAZOLE IN THE MALE F344 RAT

1. The toxicokinetics and metabolism of 4-methylimidazole (4-MZ) have been studied in the male F344 rat using C-14 radiolabelled compound. R adioactivity in plasma and urine was profiled by hplc. 2. After gavage administration of 50 mg/kg, about 85% of the administered radioactivi ty was recovered in urine within 48 h. The majority of the radioactivi ty in urine or plasma was associated with the parent compound and only one minor hydrophilic metabolite was present in urine and in plasma. Elimination of radioactivity via fecal, biliary or respiration was neg ligible. 3. Elimination of 4-MZ after an i.v. dose of 5 mg/kg can be d escribed by a two-compartment process with an estimated half-life of 1 .8 h and an estimated apparent volume of distribution of 2.3 litre/kg. 4. After gavage at doses of 5, 50 and 150 mg/kg, 4-MZ was readily abs orbed with a estimated bioavailability of 60-70%. 5. Urinary excretion data indicated that renal clearance of 4-MZ accounted for about 80% o f total body plasma clearance. Based on the estimated AUC of metabolit e and the estimated renal clearance of 4-MZ, the formation of metaboli te and the renal clearance of 4-MZ appeared to be a saturable process.