Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans.
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.
Vincent
Stella H
SH
Merck Research Laboratories, RY 80-141, P.O. Box 2000, Rahway, NJ 07065, USA. Stella_Vincent@Merck.com
Reed
James R
JR
Bergman
Arthur J
AJ
Elmore
Charles S
CS
Zhu
Bing
B
Xu
Shiyao
S
Ebel
David
D
Larson
Patrick
P
Zeng
Wei
W
Chen
Li
L
Dilzer
Stacy
S
Lasseter
Kenneth
K
Gottesdiener
Keith
K
Wagner
John A
JA
Herman
Gary A
GA
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
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