Sitagliptin 5403269 215716114 2008-05-29T11:43:32Z DOI bot 6652755 Citation maintenance. Initiated by [[User:Tarun2k|Tarun2k]]. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. {{drugbox | image = Sitagliptin.svg | image2 = Sitagliptin 3D.png | IUPAC_name = (3''R'')-3-amino-1-[9-(trifluoromethyl)-<br />1,4,7,8-tetrazabicyclo[4.3.0]nona-6,8-d ien-4-yl]-<br />4-(2,4,5-trifluorophenyl)butan-1-one | width=254 | CAS_number = 790712-60-6 | ATC_prefix = A10 | ATC_suffix = BH01 | PubChem = 4369359 | DrugBank = | C = 16 |H = 15 |N = 5 |O = 1 |F = 6 | molecular_weight = 407.314 [[Gram|g]]/[[Mole (unit)|mol]] | bioavailability = 87% | protein_bound = 38% | metabolism = [[Liver|Hepatic]] ([[CYP3A4]]- and [[CYP2C8]]-mediated) | elimination_half-life = 8 to 14 hours<ref name=Herman>{{cite journal | author = Herman G, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, Snyder K, Hilliard D, Tanen M, Tanaka W, Wang A, Zeng W, Musson D, Winchell G, Davies M, Ramael S, Gottesdiener K, Wagner J | title = 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. | journal = Clin Pharmacol Ther | volume = 78 | issue = 6 | pages = 675&ndash;88 | year = 2005 | pmid = 16338283 | doi = 10.1016/j.clpt.2005.09.002}}</ref> | excretion = [[Kidney|Renal]] (80%)<ref name=Herman/> | pregnancy_US = B | licence_EU = Januvia | licence_US = Sitagliptin | legal_UK = POM | legal_US = Rx-only | routes_of_administration = Oral }} '''Sitagliptin''' ([[International Nonproprietary Name|INN]]; previously identified as '''MK-0431''', trade name '''Januvia''') is an oral antihyperglycemic ([[anti-diabetic drug]]) of the [[DPP-4 inhibitors|dipeptidyl peptidase-4 (DPP-4) inhibitor]] class. This enzyme-inhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as [[metformin]] or a [[thiazolidinedione]]) for treatment of [[diabetes mellitus type 2]]. The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values. ==Adverse effects== In [[clinical trial]]s, [[adverse drug reaction|adverse effects]] were as common with sitagliptin (whether used alone or with [[metformin]] or [[pioglitazone]]) as they were with [[placebo]], except for [[nausea]] and [[common cold]]-like symptoms, which were more common with sitagliptin.<ref name=RxList>{{cite web | url = http://www.rxlist.com/cgi/generic/januvia_ad.htm | title = Januvia Side Effects & Drug Interactions | year = 2007 | accessdate = 2007-11-28 | publisher = RxList.com}}</ref> There is no [[statistical significance|significant]] difference in the occurrence of [[hypoglycemia]] between placebo and sitagliptin.<ref name=RxList/> ==History== Sitagliptin was approved by the [[United States|U.S.]] [[Food and Drug Administration]] (FDA) on October 17, 2006<ref name=FDAapproval> {{cite press release | title = FDA Approves New Treatment for Diabetes | publisher = U.S. Food and Drug Administration | date = October 17, 2006 | url = http://www.fda.gov/bbs/topics/NEWS/2006/NEW01492.html | accessdate = 2006-10-17 }}</ref> and is marketed in the US as '''Januvia''' by [[Merck & Co.]] On April 2, 2007, the FDA approved an oral combination of sitagliptin and [[metformin]] marketed in the US as '''Janumet'''. ==Mechanism== {{see also|Dipeptidyl peptidase-4 inhibitors}} Sitagliptin works to [[competitive inhibition|competitively inhibit]] the [[enzyme]] dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the [[incretin]]s [[GLP-1]] and GIP, [[gastrointestinal hormone]] that are released in response to a meal.<ref>{{cite journal | author = Herman G, Bergman A, Liu F, Stevens C, Wang A, Zeng W, Chen L, Snyder K, Hilliard D, Tanen M, Tanaka W, Meehan A, Lasseter K, Dilzer S, Blum R, Wagner J | title = Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. | journal = J Clin Pharmacol | volume = 46 | issue = 8 | pages = 876&ndash;86 | year = 2006 | pmid = 16855072 | doi = 10.1177/0091270006289850}}</ref> By preventing GLP-1 and GIP inactivation, GLP-1 and GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminishes thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia) which is seen with some other oral hypoglycemic agents. Sitagliptin incorporates a beta amino acid moiety that allows for a more favorable fit into the active site of DPP-4 as compared to the normal incretin substrates. The trifluorophenyl moiety also fits into a hydrophobic region of the active site.{{Fact|date=January 2008}} ==See also== *[[Dipeptidyl peptidase-4]] ==References== {{reflist}} ==External links== *[http://www.januvia.com/ Official website] *[http://www.merck.com/newsroom/press_releases/research_and_development/2006_0215.html Merck Announces FDA Acceptance of New Drug Application for JANUVIA] - Merck press release. *[http://www.forbes.com/2004/01/26/cx_mh_rl_diabetestearsheet_5.html The race to get DPP-4 inhibitors to market] - Forbes.com *[http://www.forbes.com/finance/2007/03/02/merck-novartis-januvia-pf-ii-in_dk_0302soapbox_inl.html Merck's March Madness] - Forbes.com * {{UTGlucagon|mk-0431}} - Sitagliptin * {{UTGlucagon|dp_iv}} - About DPP-4 {{Oral hypoglycemics}} {{Merck&Co}} [[Category:Dipeptidyl peptidase-4 inhibitors]] [[Category:Anti-diabetic drugs]] [[Category:Organofluorides]] [[de:Sitagliptin]]