TY - JOUR T1 - Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. AU - Herman,Gary A, AU - Stevens,Cathy, AU - Van Dyck,Kristien, AU - Bergman,Arthur, AU - Yi,Bingming, AU - De Smet,Marina, AU - Snyder,Karen, AU - Hilliard,Deborah, AU - Tanen,Michael, AU - Tanaka,Wesley, AU - Wang,Amy Q, AU - Zeng,Wei, AU - Musson,Donald, AU - Winchell,Gregory, AU - Davies,Michael J, AU - Ramael,Steven, AU - Gottesdiener,Keith M, AU - Wagner,John A, PY - 2005/05/04/received PY - 2005/09/01/accepted PY - 2005/12/13/pubmed PY - 2006/4/28/medline PY - 2005/12/13/entrez SP - 675 EP - 88 JF - Clinical pharmacology and therapeutics JO - Clin Pharmacol Ther VL - 78 IS - 6 N2 - BACKGROUND: Sitagliptin (MK-0431 [(2R)-4-oxo-4-(3-[trifluoromethyl]-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7[8H]-yl)-1-(2,4,5-trifluorophenyl)butan-2-amine]) is an orally active, potent, and selective inhibitor of dipeptidyl peptidase IV (DPP-IV) currently in phase III development for the treatment of type 2 diabetes. METHODS: Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of sitagliptin (1.5-600 mg) in healthy male volunteers. RESULTS: Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. Renal clearance of sitagliptin averaged 388 mL/min and was largely uninfluenced by the dose administered. The area under the plasma concentration-time curve for sitagliptin increased in an approximately dose-dependent manner and was not meaningfully influenced by food. Single doses of sitagliptin markedly and dose-dependently inhibited plasma DPP-IV activity, with approximately 80% or greater inhibition of DPP-IV activity occurring at 50 mg or greater over a 12-hour period and at 100 mg or greater over a 24-hour period. Compared with placebo, sitagliptin produced an approximately 2-fold increase in postmeal active glucagon-like peptide 1 levels. Sitagliptin was well tolerated and was not associated with hypoglycemia. CONCLUSIONS: This study provides proof of pharmacologic characteristics for sitagliptin in humans. By inhibiting plasma DPP-IV activity, sitagliptin increases the postprandial rise in active glucagon-like peptide 1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen. SN - 0009-9236 UR - https://www.unboundmedicine.com/medline/citation/16338283/Pharmacokinetics_and_pharmacodynamics_of_sitagliptin_an_inhibitor_of_dipeptidyl_peptidase_IV_in_healthy_subjects:_results_from_two_randomized_double_blind_placebo_controlled_studies_with_single_oral_doses_ L2 - https://doi.org/10.1016/j.clpt.2005.09.002 DB - PRIME DP - Unbound Medicine ER -