In vitro, ERTUGLIFLIZIN (PF-04971729) inhibits SGLT2 more than 2000 times more than SGLT1 [3].

In the later stages of FXR, ertugliflozin (PF-04971729) displays concentration-dependent glycosuria [3].

Absorption, Distribution and Excretion
Following a single dose of 5 mg and 15 mg eragliflozin in an empty stomach, the median time to peak concentration (Tmax) was 1 hour. The peak plasma concentration (Cmax) and area under the curve (AUC) of eragliflozin both increased proportionally with the dose. After a 15 mg dose, Cmax was 268 ng/mL and AUC was 1193 ng·h/mL. The absolute oral bioavailability of eragliflozin after a 15 mg dose is approximately 100%, but has been reported to range from 70% to 90%. Compared to an empty stomach, a high-fat, high-calorie diet decreased eragliflozin's Cmax by 29% and prolonged Tmax by 1 hour, but did not change AUC. The observed effects of food on the pharmacokinetics of eragliflozin are not considered clinically significant; eragliflozin can be taken with or without food. Following oral administration of [¹⁴C]-apagliflozin solution to healthy subjects, approximately 40.9% and 50.2% of drug-related radioactivity were excreted in feces and urine, respectively. Only 1.5% of the administered dose was excreted unchanged in urine, and 33.8% in feces, likely due to the excretion of glucuronide metabolites via bile, followed by hydrolysis to form the unchanged compound. The volume of distribution after oral administration was 215.3 L. The mean steady-state volume of distribution after intravenous administration of apagliflozin was 85.5 L. The apparent total plasma clearance after a single 15 mg dose of apagliflozin was 178.7 mL/min. The mean systemic plasma clearance after intravenous administration of a 100 µg dose was 11.2 L/hr. Metabolism/Metabolites Iragliflozin is primarily metabolized via UGT1A9 and UGT2B7-mediated O-glucuronidation to produce two pharmacologically inactive glucuronides. Approximately 12% of the drug is metabolized via CYP-mediated oxidative metabolism. Multiple metabolites have been detected in plasma, feces, and urine. In plasma, the active pharmaceutical ingredient of iragliflozin constitutes the major component of the administered dose. Biological Half-Life The terminal elimination half-life of iragliflozin is 11 to 17 hours. Based on population pharmacokinetic analysis, the mean elimination half-life in patients with type 2 diabetes and normal renal function is estimated to be 16.6 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no clinical information regarding the use of ertugliflozin during lactation. Ertugliflozin has a 94% protein binding rate in plasma, making it unlikely to enter breast milk in clinically significant amounts. Due to the theoretical risk to the developing kidneys of the infant, the manufacturer does not recommend the use of ertugliflozin during lactation. Alternative medications are recommended, especially when breastfeeding newborns or preterm infants.
◉ Effects on Breastfed Infants
No relevant published information was found as of the revision date.
◉ Effects on Lactation and Breast Milk
No relevant published information was found as of the revision date.

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Protein Binding
Ertugliflozin binds to plasma proteins at a rate of 93.6%. Plasma protein binding is not correlated with ertugliflozin plasma concentrations and is not significantly altered in patients with impaired renal or hepatic function. The blood concentration to plasma concentration ratio of apagliflozin is 0.66.

[1]. Mascitti V, et al. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo[3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J Med Chem. 2011 Apr 28;54(8):2952-60.
[2]. Miao Z, et al. Pharmacokinetics, metabolism, and excretion of the antidiabetic agent ertugliflozin (PF-04971729) in healthy male subjects. Drug Metab Dispos. 2013 Feb;41(2):445-56.
[3]. Kalgutkar AS, et al. Preclinical species and human disposition of PF-04971729, a selective inhibitor of the sodium-dependent glucose cotransporter 2 and clinical candidate for the treatment of type 2 diabetes mellitus. Drug Metab Dispos. 2011 Sep;39(9):1609-19.

Ertugliflozin is a diarylmethane compound. Ertugliflozin is a sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor used to treat type 2 diabetes. Its mechanism of action is to block the reabsorption of glucose by the glomeruli. Ertugliflozin was first approved by the U.S. Food and Drug Administration (FDA) in December 2017 and by the European Commission in March 2018. See also: Ertugliflozin pyridinecarboxylate (active ingredient); Ertugliflozin; Metformin hydrochloride (ingredient); Ertugliflozin; Sitagliptin phosphate (ingredient). Indications: Ertugliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus (T2DM). It may also be used in combination with metformin or sitagliptin. Ertugliflozin is not recommended for improving glycemic control in patients with type 1 diabetes. Steglatro is indicated for adults aged 18 years and older with type 2 diabetes as an adjunct to diet and exercise to improve glycemic control; it can also be used as monotherapy in patients who are not suitable for metformin due to intolerance or contraindications; or in combination with other diabetes medications. Treatment of Type 2 Diabetes

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Mechanism of Action
The kidneys play an indispensable role in glucose homeostasis. After plasma glucose is filtered into the urine by nephrons, most of it is reabsorbed by two sodium-dependent glucose cotransporters (SGLTs)—SGLT1 and SGLT2—expressed in the proximal tubules. More specifically, SGLT2 is responsible for 80-90% of renal glucose reabsorption, while SGLT1 is responsible for the remaining 10-20%. Under physiological conditions, less than 1% of glucose is excreted in the urine. When blood glucose levels rise, SGLTs become saturated, and the kidney's threshold for urinary glucose excretion increases. The kidneys respond to the increased urinary glucose threshold by increasing glucose reabsorption and improving maximal glucose reabsorption capacity. Iragliflozin is an SGLT2 inhibitor that reduces the reabsorption of filtered glucose by the kidneys, lowers the renal glucose threshold, and thus increases urinary glucose excretion.

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Pharmacodynamics
Iragliflozin can dose-dependently increase urinary glucose excretion and urine volume in patients with type 2 diabetes.

C22H25CLO7

436.89

436.128

1210344-57-2

Ertugliflozin L-pyroglutamic acid;1210344-83-4;Ertugliflozin-d5;1298086-22-2

44814423

White to off-white solid powder

1.5±0.1 g/cm3

630.5±55.0 °C at 760 mmHg

335.1±31.5 °C

0.0±1.9 mmHg at 25°C

1.652

6.49

4

7

6

30

586

5

ClC1C([H])=C([H])C(=C([H])C=1C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])C([H])([H])[H])[C@]12[C@@]([H])([C@]([H])([C@@]([H])([C@](C([H])([H])O[H])(C([H])([H])O1)O2)O[H])O[H])O[H]

MCIACXAZCBVDEE-CUUWFGFTSA-N

InChI=1S/C22H25ClO7/c1-2-28-16-6-3-13(4-7-16)9-14-10-15(5-8-17(14)23)22-20(27)18(25)19(26)21(11-24,30-22)12-29-22/h3-8,10,18-20,24-27H,2,9,11-12H2,1H3/t18-,19-,20+,21-,22-/m0/s1

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.76 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (4.76 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (4.76 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)