The metabolism of zomepirac sodium. I. Disposition in laboratory animals and man.

Zomepirac sodium (ZS) is an orally active, nonnarcotic, analgesic agent. The disposition and pharmacokinetics of zomepirac (Z) were studied in rats, mice, rabbits, hamsters, rhesus monkeys, and healthy human subjects. Z was rapidly and completely absorbed by all animal species and man. Dose-related linear increases in the area under the curve for plasma Z vs. time were noted after increasing po doses of ZS to mice (2.5--7.5 mg/kg), rats (0.5--10 mg/kg), and rhesus monkeys (5--40 mg/kg). Daily administration of ZS to rats (10 mg/kg/day for 10 days) caused no biologically significant changes in the pharmacokinetic profile for Z. Assessment of Z's absolute bioavailability in monkeys (10 mg/kg, iv vs. po) indicated that po doses of ZS were completely bioavailable (F = 1.12 +/- 0.40). Plasma clearance ranged from ca. 4.5 ml/min/kg for the female hamster, rhesus monkey, and man to as low as 0.30 ml/min/kg for rats, mice, and rabbits. Terminal elimination half-lives averaged 5.3--6.6 hr for mouse, 2.8--6.5 hr for rat, 2.5 hr for rabbit, 2.3 hr for hamster, 12.7--25.5 hr for rhesus monkey, and 4 hr for man. The major route of excretion for Z and its metabolites was via the kidneys for all animals and man with the balance appearing in feces. Biliary excretion was qualitatively observed in rhesus monkeys and quantitated in rats (23.6% of dose in 27 hr). Formation of the acyl glucuronide of Z was the major metabolic pathway in man and rhesus monkey, was substantial in the mouse, was very minor in the rat and rabbit, and was nonexistent in the hamster. Rat, mouse, and hamster hydroxylate the 4-methyl group on the pyrrole ring to give hydroxyzomepirac (a biologically inactive metabolite), a minor metabolite in man and nonexistent in the rhesus monkey. The rodents also cleave Z to form 4-chlorobenzoic acid and its conjugates, minor metabolites in man and rhesus monkey.