DISPOSITION AND METABOLISM OF THE HYPOGLYCEMIC AGENT PIOGLITAZONE IN RATS

The disposition and metabolism of [H-3]pioglitazone was determined in male rats after oral administration. The peak plasma concentration of 10 mu g/ml occurred 1 hr after dosing at 10 mg/kg po; the apparent pla sma terminal half-life was 7.5 hr. Most of the radioactivity in plasma up to 8 hr after dosing was due to the parent drug. Pioglitazone was highly protein-bound in plasma; only 1-2% was free at concentrations o f 0.1-10 mu g/ml. Within 3 days after oral administration to bile duct -cannulated rats, 36% and 15% of the oral dose was recovered in the bi le and urine, respectively. The pattern of biliary and urinary metabol ites was similar. A total of eight metabolites were isolated and ident ified on the basis of NMR spectroscopy and MS. Metabolites resulting f rom hydroxylation of either carbon adjacent to the pyridine ring were conjugated with glucuronic acid (M7) or sulfuric acid (M6). The metabo lite hydroxylated on the terminal carbon of the ethyl side chain was f urther oxidized to the carboxylic acid derivative (M3). Oxidative loss of the terminal carbon led to a nicotinic acid derivative (M2) and lo ss of both carbon atoms to the corresponding 3-hydroxypyridine (M9) de rivative that was excreted as the sulfate conjugate (M8). The two carb oxylic acid metabolites were also conjugated with taurine (M4 and M5).