TY - JOUR T1 - Metabolism And Excretion of the Dipeptidyl Peptidase 4 Inhibitor [<sup>14</sup>C]Sitagliptin in Humans JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 533 LP - 538 DO - 10.1124/dmd.106.013136 VL - 35 IS - 4 AU - Stella H. Vincent AU - James R. Reed AU - Arthur J. Bergman AU - Charles S. Elmore AU - Bing Zhu AU - Shiyao Xu AU - David Ebel AU - Patrick Larson AU - Wei Zeng AU - Li Chen AU - Stacy Dilzer AU - Kenneth Lasseter AU - Keith Gottesdiener AU - John A. Wagner AU - Gary A. Herman Y1 - 2007/04/01 UR - http://dmd.aspetjournals.org/content/35/4/533.abstract N2 - The metabolism and excretion of [14C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 μCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing &lt;1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8. The American Society for Pharmacology and Experimental Therapeutics ER -