IC50: 19 nM (porcine gastric H+,K+-ATPase, at pH 6.5)[2]

Porcine stomach H+,K+-ATPase activity is seen in response to vonoprazan (0.1 nM–10 μM; 30 minutes) in a concentration-dependent manner[2]. Even at 500 times higher concentrations than their IC50 values against stomach H+,K+-ATPase activity, vonoprazan does not inhibit Na+,K+-ATPase activity[2].

Rats' baseline and 2-deoxy-D-glucose (2DG, 200 mg/kg sc)-stimulated stomach acid production is totally inhibited by vonoprazan (1-4 mg/kg; po) at a dose of 4 mg/kg[2].

Proton Potassium Adenosine Triphosphatase (H+,K+-ATPase) Inhibitory Activity Test [1]
Accordinpg to the method of Wallmark et al., a gastric mucosal membrane microsomal fraction was prepared from the stomach of swine. First, the stomach was removed, washed with tap water, and immersed in 3 mol/L brine, and the surface of the mucosal membrane was wiped with a paper towel. The gastric mucosal membrane was detached, chopped, and homogenized in a 0.25 mol/L saccharose solution (pH 6.8) containing 1 mmol/L EDTA and 10 mmol/L tris-hydrochloric acid using polytron (Kinematica). The obtained homogenate was centrifuged at 20000g for 30 min and the supernatant was centrifuged at 100000g for 90 min. The precipitate was suspended in 0.25 mol/L saccharose solution, superimposed on a 0.25 mol/L saccharose solution containing 7.5% Ficoll, and centrifuged at 100000g for 5 h. The fraction containing the interface between the both layers was recovered, and centrifugally washed with 0.25 mol/L saccharose solution. The obtained microsomal fraction was used as a proton, potassium adenosine triphosphatase standard product. To 40 μL of a 50 mmol/L HEPES-Tris buffer (5 mmol/L magnesium chloride, 10 mmol/L potassium chloride, 10 μmol/L valinomycin, pH 6.5) containing 2.5 μg/mL (based on the protein concentration) of the enzyme standard product was added a test compound (5 μL) dissolved in a 10% aqueous dimethyl sulfoxide solution, and the mixture was incubated at 37 °C for 30 min. The enzyme reaction was started by adding 5 μL of a 2 mmol/L adenosine triphosphate Tris salt solution (50 mmol/L HEPES-Tris buffer (5 mmol/L magnesium chloride, pH 6.5)). The enzyme reaction was carried out at 37 °C for 20 min, and 15 μL of a malachite green solution (0.12% malachite green solution in sulfuric acid (2.5 mol/L), 7.5% ammonium molybdate, and 11% Tween 20 were mixed at a ratio of 100:25:2) was added to quench the reaction. After the mixture was allowed to stand at room temperature for 15 min, the resulting reaction product of inorganic phosphorus with malachite green was colorimetrically determined at a wavelength of 610 nm. In addition, the amount of the inorganic phosphoric acid in the reaction solution free of potassium chloride was measured in the same manner, which was subtracted from the inorganic phosphoric acid amount in the presence of potassium chloride to determine the H+,K+-ATPase activity. The inhibitory rate (%) was determined from the activity value of the control and the activity values of various concentrations of the test compound, and the 50% inhibitory concentration (IC50) of the H+,K+-ATPase activity was determined.

Animal/Disease Models: Male 7- or 8weeks old SD (Sprague-Dawley) rat[2]
Doses: 0.5, 1, 2, and 4 mg/kg
Route of Administration: Oral administration
Experimental Results: Inhibited basal gastric acid secretion in a dose-dependent manner.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of vonoprazan during breastfeeding. Because of liver damage that occurred in nursing rodents, the manufacturer recommends that nursing mothers should pump and discard human milk while taking and for 2 days after the last dose. An alternate drug may be preferred.

◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
In healthy subjects, the plasma protein binding of vonoprazan ranges from 85% to 88%. At plasma concentrations between 0.1 and 10 mcg/mL, the plasma protein binding of vonoprazan is independent of concentration.

[1]. Discovery of a novel pyrrole derivative 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine fumarate (TAK-438) as a potassium-competitive acid blocker (P-CAB). J Med Chem, 2012, 55(9), 4446-4456.

[2]. 1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases. J Pharmacol Exp Ther, 2010, 335(1), 231-238.

Vonoprazan Fumarate is the fumarate salt form of vonoprazan, a pyrrole derivative and reversible potassium-competitive acid blocker (P-CAB), with potential antacid activity. Upon administration, vonoprazan specifically and competitively binds to the gastric hydrogen-potassium ATPase (H+/K+ ATPase) proton pump at or, more likely, near its potassium ion (K+) binding site and sterically inhibits K+ binding. This blocks the activation of the H+/K+ ATPase by K+, inhibits the proton pump and prevents gastric acid secretion, thereby lowering gastric acid levels.
See also: Vonoprazan (has active moiety); Amoxicillin; clarithromycin; vonoprazan fumarate (component of); Amoxicillin; vonoprazan fumarate (component of).

C21H20FN3O6S

461.46

461.105

C, 54.66; H, 4.37; F, 4.12; N, 9.11; O, 20.80; S, 6.95

881681-01-2

Vonoprazan;881681-00-1;Vonoprazan hydrochloride;1957202-44-6

45375887

White to off-white solid powder

3.829

3

9

7

32

629

0

CNCC1=CN(C(=C1)C2=CC=CC=C2F)S(=O)(=O)C3=CN=CC=C3.C(=C/C(=O)O)\C(=O)O

ROGSHYHKHPCCJW-WLHGVMLRSA-N

InChI=1S/C17H16FN3O2S.C4H4O4/c1-19-10-13-9-17(15-6-2-3-7-16(15)18)21(12-13)24(22,23)14-5-4-8-20-11-14;5-3(6)1-2-4(7)8/h2-9,11-12,19H,10H2,1H3;1-2H,(H,5,6)(H,7,8)/b;2-1+

(E)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-N-methylmethanamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO: 50 mg/mL (108.35 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.42 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 25.0 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: ≥ 2.5 mg/mL (5.42 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 25.0 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: ≥ 2.5 mg/mL (5.42 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 25.0 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.)