Five healthy male human subjects were administered 200 mg oral solution doses of zomepirac-14C sodium. Plasma and urine samples were analyzed for zomepirac, hydroxyzomepirac, and zomepirac glucuronide. Zomepirac was the major circulating compound, with zomepirac glucuronide and hydroxyzomepirac accounting for the remainder of the radioactivity. Elimination half-lives for zomepirac, zomepirac glucuronide, and hydroxyzomepirac were 7.6, 8.2, and 7.8 hours, respectively. The dose was completely recovered in the urine (95 per cent in 72 hours). Zomepirac glucuronide constituted up to 90 per cent of the urinary radioactivity, with zomepirac and hydroxyzomepirac about 5 per cent each. The urinary zomepirac was probably present as a result of hydrolysis of zomepirac glucuronide. The plasma clearance of zomepirac was 189 +/- 23 ml/min. The metabolites were cleared by the kidney at rates of 343 +/- 88 ml/min (zomepirac glucuronide) and 339 +/- 88 ml/min (hydroxyzomepirac). Thus, metabolic clearance appears to be the sole mode of zomepirac elimination. The metabolites are then rapidly cleared by the kidneys.

1. The disposition and pharmacokinetics of bepridil (Bp) were studied in mouse, rat, rabbit, rhesus monkey, and man. Bp was essentially completely absorbed by all species. 2. Maximum plasma Bp concentrations were achieved within 2 h of drug administration. Linear but non-proportional, dose-related increases in the area under the curve (AUC) for plasma Bp vs. time were noted after increasing oral doses of Bp.HCl to rats (30-300 mg/kg) and monkeys (25-200 mg/kg). 3. Daily administration of Bp.HCl to rats (100 mg/kg per day for 15 days) and monkeys (200 mg/kg per day for 13 days) produced no statistically significant changes in Bp pharmacokinetic parameters. 4. Oral plasma clearance (CLp) of Bp was very low in man (ca. 0.93 l/h per kg) compared to experimental animals (14.8-63.8 l/h per kg). Terminal elimination half-lives were 1.5-2.0 h for mouse and rat, ca. 4.4 h for monkey and ca. 48 h for man. 5. Bp and a total of 12 metabolites were identified and quantified. Metabolite formation in the five species was adequately described by four interrelated pathways, namely, aromatic hydroxylation, followed by N-dealkylation, N-debenzylation, and N-acetylation. Metabolites produced by this pathway included 4-hydroxy-Bp, N-benzyl-4-aminophenol, 4-aminophenol, and N-acetyl-4-aminophenol. Comparison of the proposed pathways revealed qualitative similarity among species.

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