Absorption, Disposition, and Metabolism of Rosiglitazone, a Potent Thiazolidinedione Insulin Sensitizer, in Humans

Rosiglitazone is a potent peroxisome proliferator-activated receptor gamma agonist that decreases hyperglycemia by reducing insulin resistance in patients with type 2 diabetes mellitus. The disposition of (14)C-labeled rosiglitazone was determined after oral and i.v. dosing of rosiglitazone solution, and the disposition of nonradiolabeled rosiglitazone was determined after oral dosing of tablets in this open-label, three-part, semirandomized, crossover study. The absorption of rosiglitazone was rapid and essentially complete, with absolute bioavailability estimated to be approximately 99% after oral tablet dosing and approximately 95% after oral solution dosing, and clearance was primarily metabolic. The time to maximal concentration of radioactivity and the elimination half-life for two metabolites in plasma were significantly longer than for rosiglitazone itself (4-6 h versus 0. 5-1 h, and ca. 5 days versus 3-7 h). Radioactivity was excreted primarily via the urine ( approximately 65%) and was excreted similarly after oral and i.v. dosing. The major routes of metabolism were N-demethylation and hydroxylation with subsequent conjugation, of which neither was affected by the route of drug administration. The major metabolites, those of intermediate importance, and nearly all of the trace metabolites in humans have been identified previously in preclinical studies. Rosiglitazone was well tolerated in all formulations.