Abstract
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 14C-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 ∼99% after oral tablet dosing and ∼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 (∼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.
Footnotes
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Send reprint requests to: Dr. Peter J. Cox, SmithKline Beecham Pharmaceuticals, The Frythe, Welwyn, Herts. AL6 9AR, UK. E-mail: Peter_J_Cox{at}sbphrd.com
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↵2 Nomenclature of metabolites. During preclinical metabolism studies (Bolton et al., 1996), metabolite structure names were not based on the IUPAC numbering system. Thus, metabolites previously designated as 3-hydroxy and 5-hydroxy should more correctly, under the IUPAC system, be designated 5-hydroxy and 3-hydroxy, respectively, a source of potential confusion. In this study, metabolites containing the IUPAC substructure 2-aminopyridinyl-5-hydroxy are referred to aspara-hydroxy metabolites, reflecting hydroxylation at a position para to the amino side chain. Similarly, metabolites containing the pyridinyl-3-hydroxy substructure are referred to as ortho-hydroxy, reflecting hydroxylation at a position ortho to the amino side chain.
- Abbreviations used are::
- LC-MS
- liquid chromatography-mass spectrometry
- LSC
- liquid scintillation counting
- SPE
- solid-phase extraction
- Cmax
- maximum observed concentration
- Tmax
- the time to reach Cmax
- AUC0-inf
- area under the plasma concentration-time curve from time zero to infinity
- Received July 27, 1999.
- Accepted April 10, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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