Sitagliptin

Absorption

Sitagliptin is 87% orally bioavailable and taking it with or without food does not affect its pharmacokinetics. Sitagliptin reaches maximum plasma concentration in 2 hours.

Toxicity

Animal studies in pregnancy have shown no adverse effects on the mother or offspring at normal doses, however these results are not always applicable to humans. There is currently a voluntary registry of fetal exposure. Animal studies at 100 times the maximum recommended human dose resulted in an increase in rib malformations. Sitagliptin is excreted in the milk of rats but it is not known if it would also be expressed in human breast milk. Because many drugs are expressed in human breast milk, the risk and benefit of prescribing the medication must be considered. There is currently a lack of safety and effectiveness data in pediatric patients. No differences in safety and efficacy were observed in geriatric patients compared to younger patients, however caution should be used in this population as they are more likely to have reduced renal function. Sitagliptin has also been associated with a 34% relative risk increase for all cause infection. There was no significant difference in patient response across sex, age, race, ethnicity, and BMI.

Description

Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, is a first-in-class oral drug launched for the treatment of type 2 diabetes. It acts by slowing the inactivation of incretins, which are endogenous peptides involved in the physiologic regulation of glucose homeostasis. Incretin hormones, including glucagonlike peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are released by the intestine throughout the day, and levels are increased in response to a meal. When blood glucose concentrations are normal or elevated,GLP-1 and GIP increase the synthesis and release of insulin from pancreatic b cells via intracellular signaling pathways involving cAMP. GLP-1 also lowers glucagon secretion from pancreatic αcells, which leads to reduced hepatic glucose production.

Originator

Merck (US)

The Uses of Sitagliptin

Labeled Sitagliptin , intended for use as an internal standard for the quantification of Sitagliptin by GC- or LC-mass spectrometry.

The Uses of Sitagliptin

Sitagliptin is a useful pharmaceutical drug. Could be useful for treating intestinal inflammation, diabetes, pre-?diabetes, impaired glucose tolerance, hepatitis, and?/or inflammatory liver disease.

What are the applications of Application

Sitagliptin is a DPP-4 inhibitor

Background

Sitagliptin is an oral dipeptidyl peptidase-4 (DPP-4) inhibitor used in conjunction with diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. The effect of this medication leads to glucose dependent increases in insulin and decreases in glucagon to improve control of blood sugar. Sitagliptin was granted FDA approval on October 16, 2006.

Indications

Sitagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is not used to treat type 1 diabetes or patients with a history of pancreatitis.
It is also used in combination with metformin or ertugliflozin.

Definition

ChEBI: Sitagliptin is a triazolopyrazine that exhibits hypoglycemic activity. It has a role as a serine proteinase inhibitor, a hypoglycemic agent, an EC 3.4.14.5 (dipeptidyl-peptidase IV) inhibitor, an environmental contaminant and a xenobiotic. It is a triazolopyrazine and a trifluorobenzene.

brand name

Januvia

Mechanism of action

Sitagliptin's mechanism of action is through inhibition of dipeptidyl peptidase-4 (DPP-4), an enzyme that acts to degrade and inactivate glucagon-like peptide-1 (GLP-1). The elevated GLP-1 level in response to sitagliptin results in increased insulin release after meals, and improved glucose tolerance.

brand name

Januvia

Pharmacokinetics

Sitagliptin inhibits DPP-4 which leads to increased levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide(GIP), decreased levels of glucagon, and a stronger insulin response to glucose.

Clinical Use

Treatment of type 2 diabetes in combination with metformin or a thiazolidinedione

Side Effects

A common side effect of Sitagliptin is headache. Low blood sugar may occur when it is taken with other diabetes medicines such as insulin or gliclazide.Sitagliptin may also have other side effects, including upper respiratory tract infections, stuffy or runny nose, sore throat stomach upset, diarrhoea, and swelling of the hands or legs. Severe can cause pancreatitis and liver problems. Serious allergic reactions are rare.

Metabolism

Sitagliptin is mostly not metabolised, with 79% of the dose excreted in the urine as the unchanged parent compound. Minor metabolic pathways are mediated mainly by cytochrome p450(CYP)3A4 and to a lesser extent by CYP2C8. After 18 hours, 81% of the dose has remained unchanged, while 2% has been N-sulfated to the M1 metabolite, 6% has been oxidatively desaturated and cyclized to the M2 metabolite, <1% glucuronidated at an unknown site to the M3 metabolite, <1% has been carbamoylated and glucuronidated to the M4 metabolite, 6% has been oxidatively saturated and cyclized to the M5 metabolite, and 2% has been hydroxylated at an unknown site to the M6 metabolite. The M2 metabolite is the cis isomer while the M5 metabolite is the trans isomer of the same metabolite.

Metabolism

Sitagliptin undergoes minimal metabolism, mainly by the cytochrome P450 isoenzyme CYP3A4, and to a lesser extent by CYP2C8.
Renal excretion of sitagliptin involves active tubular secretion; it is a substrate for organic anion transporter-3 and P-glycoprotein.