title: Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans.
abstract: The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. 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 <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.
authors.affiliation: Merck Research Laboratories, RY 80-141, P.O. Box 2000, Rahway, NJ 07065, USA. Stella_Vincent@Merck.com
authors.forename: Stella H
authors.initials: SH
authors.lastname: Vincent
authors.forename: James R
authors.initials: JR
authors.lastname: Reed
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Bergman
authors.forename: Charles S
authors.initials: CS
authors.lastname: Elmore
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.forename: Shiyao
authors.initials: S
authors.lastname: Xu
authors.forename: David
authors.initials: D
authors.lastname: Ebel
authors.forename: Patrick
authors.initials: P
authors.lastname: Larson
authors.forename: Wei
authors.initials: W
authors.lastname: Zeng
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Stacy
authors.initials: S
authors.lastname: Dilzer
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lasseter
authors.forename: Keith
authors.initials: K
authors.lastname: Gottesdiener
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Gary A
authors.initials: GA
authors.lastname: Herman
mesh_terms: D000243:Adenosine Deaminase / Q000378:metabolism; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D001711:Biotransformation; D002250:Carbon Radioisotopes; D003500:Cyclization; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D005243:Feces / Q000737:chemistry; D020719:Glucuronides / Q000378:metabolism; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011719:Pyrazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D011994:Recombinant Proteins / Q000378:metabolism; D012016:Reference Values; D000068900:Sitagliptin Phosphate; D013463:Sulfuric Acid Esters / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D058892:Adenosine Deaminase Inhibitors; D002250:Carbon Radioisotopes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004791:Enzyme Inhibitors; D020719:Glucuronides; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D011719:Pyrazines; D011994:Recombinant Proteins; D013463:Sulfuric Acid Esters; D014230:Triazoles; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000243:Adenosine Deaminase; D000068900:Sitagliptin Phosphate