| Item |
Information |
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Drug Groups
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approved; investigational |
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Description
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Sitagliptin is a new oral hypoglycemic (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. This enzyme-inhibiting drug is to be used either alone or in combination with metformin or a thiazolidinedione for control of type 2 diabetes mellitus. The drug works to competitively inhibit a protein/enzyme, dipeptidyl peptidase 4 (DPP-4), that results in an increased amount of active incretins (GLP-1 and GIP), reduced amount of release of glucagon (diminishes its release) and increased release of insulin. |
| Indication |
For use as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Also for use in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a PPARγ agonist (e.g., thiazolidinediones) when the single agent alone, with diet and exercise, does not provide adequate glycemic control. |
| Pharmacology |
Sitagliptin is an orally-active member of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs. The benefit of this medicine is expected to be its lower side-effects of hypoglycemia in the control of blood glucose values. The drug works to diminish the effects of a protein/enzyme (by the inhibition of this protein/enzyme) on the pancreas at the level of release of glucagon (diminishes its release) and at the level of insulin (increases its synthesis and release) until blood glucose levels are restored toward normal, in which case the protein/enzyme-enzyme inhibitor becomes less effective and the amounts of insulin released diminishes thus diminishing the "overshoot" of hypoglycemia seen in other oral hypoglycemic agents. |
| Affected Organisms |
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Humans and other mammals |
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| Biotransformation |
Sitagliptin does not undergo extensive metabolism. In vitro studies indicate that the primary enzyme responsible for the limited metabolism of sitagliptin was CYP3A4 (oxidation), with contribution from CYP2C8. |
| Absorption |
Rapidly absorbed following oral administration, with an absolute bioavailability of 87%. |
| Half Life |
12.4 hours |
| Protein Binding |
The fraction of sitagliptin reversibly bound to plasma proteins is low (38%). |
| Elimination |
Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination. Following administration of an oral [14C]sitagliptin dose to healthy subjects, approximately 100% of the administered radioactivity was eliminated in feces (13%) or urine (87%) within one week of dosing. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. |
| Distribution |
* 198 L [healthy subjects] |
| Clearance |
* renal cl=350 mL/min [Healthy subjects receiving 100?mg oral dose] |
| References |
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Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang AQ, Zeng W, Musson D, Winchell G, Davies MJ, Ramael S, Gottesdiener KM, Wagner JA: 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. Clin Pharmacol Ther. 2005 Dec;78(6):675-88.
[Pubmed]
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Herman GA, Bergman A, Liu F, Stevens C, Wang AQ, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan AG, Lasseter K, Dilzer S, Blum R, Wagner JA: Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J Clin Pharmacol. 2006 Aug;46(8):876-86.
[Pubmed]
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Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP: Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008 Feb;24(2):489-96.
[Pubmed]
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Pratley RE, Salsali A: Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin. 2007 Apr;23(4):919-31.
[Pubmed]
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Bergman A, Ebel D, Liu F, Stone J, Wang A, Zeng W, Chen L, Dilzer S, Lasseter K, Herman G, Wagner J, Krishna R: Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers. Biopharm Drug Dispos. 2007 Sep;28(6):315-22.
[Pubmed]
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Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C: Emerging role of dipeptidyl peptidase-4 inhibitors in the management of type 2 diabetes. Vasc Health Risk Manag. 2008;4(4):753-68.
[Pubmed]
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