Tenatoprazole
Encyclopedia
Tenatoprazole discovered in Japan
, is a proton pump inhibitor
indicated for the treatment of reflux oesophagitis and peptic ulcer
. Discovered by Mitsubishi Pharma, it is an imidazopyridine
derivative and has an imidazopyridine ring in place of the benzimidazole
moiety found in other proton pump inhibitors. It is activated slowly and its inhibition is said to be resistant to reversal. Tenatoprazole has an extended plasma half-life which makes it more effective in the treatment of nocturnal acid breakthrough than esomeprazole
.
of the proton pump inhibitor (PPI) class, which is converted to the active sulfenamide
or sulfenic acid
by acid in the secretory canaliculus of the stimulated parietal cell of the stomach. This active species binds to luminally accessible cysteines of the gastric H+,K+ -ATPase resulting in disulfide
formation and acid secretion inhibition. Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg(-1) of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg(-1) of the enzyme at 2 h after IV administration. The binding sites of tenatoprazole were in the TM5/6 region at Cys813 and Cys822 as shown by tryptic and thermolysin digestion of the ATPase labeled by tenatoprazole. Decay of tenatoprazole binding on the gastric H+,K+ -ATPase consisted of two components. One was fast, with a half-life of 3.9 h due to reversal of binding at cysteine 813, and the other was a plateau phase corresponding to ATPase turnover reflecting binding at cysteine 822 that also results in sustained inhibition in the presence of reducing agents in vitro. The stability of inhibition and the long plasma half-life of tenatoprazole should result in prolonged inhibition of acid secretion as compared to omeprazole
. The bioavailability of tenatoprazole was twofold greater in the (S)-tenatoprazole sodium salt hydrate form as compared to the free form due to differences in the crystal structure and hydrophobic nature of the two forms.
Pharmacodynamic studies on the same subjects showed an increase of intragastric pH with tenatoprazole 40 mg daily for seven days, significantly higher (p<0.05) than that observed with the same regimen of esomeprazole, the median pH being 4.6±0.9 and 4.2±0.8, respectively. In addition, the time spent above pH 4 at night after tenatoprazole administration was significantly longer than that observed with esomeprazole. The intragastric pH during the night was similarly higher (4.7±1.1 Units with tenatoprazole and 3.6±1.4 Units with esomeprazole, p<0.01), indicating better acid control.
A more recent pharmacodynamic and pharmacokinetic investigation did confirm and extended previous data showing the prolonged duration of acid suppression with tenatoprazole. The proportion of healthy volunteers spending at least 16 h above pH 4 in the 24 h period was remarkably higher with tenatoprazole than with esomeprazole (81.5% versus 34.5%, p<0.001) while the proportion of subjects with NAB was lower (73.1% versus 93.1%, p=0.06), although the difference fell short of statistical significance. Even 3 days after treatment was discontinued, mean 24 h pH, and percentage of time at pH>3 and pH>4 were significantly higher with tenatoprazole, indicating a sustained control of intragastric acidity with this novel PPI compared to esomeprazole. After 7 days repeated dosing, the maximal plasma concentration of tenatoprazole was almost six times higher than that of esomeprazole while AUC was 32 times higher. A significant correlation between AUC and percentage of time intragastric pH>4 was observed with tenatoprazole not only during but also after stopping treatment.
In summary, available studies point out both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. Since this last compound provides – amongst the members of the class — the most effective control of intragastric pH whatever the parameter considered, it is conceivable that tenatoprazole could similarly be better than the other existing PPIs. Tenatoprazole (as well as its S-isomer) appears a promising PPI for the treatment of acid-related diseases, where it has the potential to address unmet clinical needs.
Japan
Japan is an island nation in East Asia. Located in the Pacific Ocean, it lies to the east of the Sea of Japan, China, North Korea, South Korea and Russia, stretching from the Sea of Okhotsk in the north to the East China Sea and Taiwan in the south...
, is a proton pump inhibitor
Proton pump inhibitor
Proton-pump inhibitors are a group of drugs whose main action is a pronounced and long-lasting reduction of gastric acid production. They are the most potent inhibitors of acid secretion available today. The group followed and has largely superseded another group of pharmaceuticals with similar...
indicated for the treatment of reflux oesophagitis and peptic ulcer
Peptic ulcer
A peptic ulcer, also known as PUD or peptic ulcer disease, is the most common ulcer of an area of the gastrointestinal tract that is usually acidic and thus extremely painful. It is defined as mucosal erosions equal to or greater than 0.5 cm...
. Discovered by Mitsubishi Pharma, it is an imidazopyridine
Imidazopyridine
The imidazopyridines are a class of drugs defined by their chemical structure. They are generally GABAA receptor agonists, however recently proton pump inhibitors in this class have been developed as well. Despite usually being similar to them in effect, they are not chemically related to...
derivative and has an imidazopyridine ring in place of the benzimidazole
Benzimidazole
Benzimidazole is a heterocyclic aromatic organic compound. This bicyclic compound consists of the fusion of benzene and imidazole. The most prominent benzimidazole compound in nature is N-ribosyl-dimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. Benzimidazole, in...
moiety found in other proton pump inhibitors. It is activated slowly and its inhibition is said to be resistant to reversal. Tenatoprazole has an extended plasma half-life which makes it more effective in the treatment of nocturnal acid breakthrough than esomeprazole
Esomeprazole
Esomeprazole is a proton pump inhibitor developed and marketed by AstraZeneca which is used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease and Zollinger-Ellison syndrome...
.
Pharmacological action
Tenatoprazole is a prodrugProdrug
A prodrug is a pharmacological substance administered in an inactive form. Once administered, the prodrug is metabolised in vivo into an active metabolite, a process termed bioactivation. The rationale behind the use of a prodrug is generally for absorption, distribution, metabolism, and...
of the proton pump inhibitor (PPI) class, which is converted to the active sulfenamide
Sulfenamide
Sulfenamides are a class of organosulfur compounds with the general formula RSNR'2, where R and R' are H, alkyl, or ary.-Preparation:Sulfenamides are usually prepared by the reaction of sulfenyl chlorides and amines:...
or sulfenic acid
Sulfenic acid
A sulfenic acid is an organosulfur compound and oxoacid with the general formula RSOH, where R ≠ H. Simple sulfenic acids, such as methanesulfenic acid, CH3SOH, are highly reactive and cannot be isolated in solution. In the gas phase the lifetime of methanesulfenic acid is about one minute...
by acid in the secretory canaliculus of the stimulated parietal cell of the stomach. This active species binds to luminally accessible cysteines of the gastric H+,K+ -ATPase resulting in disulfide
Disulfide
In chemistry, a disulfide usually refers to the structural unit composed of a linked pair of sulfur atoms. Disulfide usually refer to a chemical compound that contains a disulfide bond, such as diphenyl disulfide, C6H5S-SC6H5....
formation and acid secretion inhibition. Tenatoprazole binds at the catalytic subunit of the gastric acid pump with a stoichiometry of 2.6 nmol mg(-1) of the enzyme in vitro. In vivo, maximum binding of tenatoprazole was 2.9 nmol mg(-1) of the enzyme at 2 h after IV administration. The binding sites of tenatoprazole were in the TM5/6 region at Cys813 and Cys822 as shown by tryptic and thermolysin digestion of the ATPase labeled by tenatoprazole. Decay of tenatoprazole binding on the gastric H+,K+ -ATPase consisted of two components. One was fast, with a half-life of 3.9 h due to reversal of binding at cysteine 813, and the other was a plateau phase corresponding to ATPase turnover reflecting binding at cysteine 822 that also results in sustained inhibition in the presence of reducing agents in vitro. The stability of inhibition and the long plasma half-life of tenatoprazole should result in prolonged inhibition of acid secretion as compared to omeprazole
Omeprazole
Omeprazole is a proton pump inhibitor used in the treatment of dyspepsia, peptic ulcer disease , gastroesophageal reflux disease , laryngopharyngeal reflux and Zollinger–Ellison syndrome...
. The bioavailability of tenatoprazole was twofold greater in the (S)-tenatoprazole sodium salt hydrate form as compared to the free form due to differences in the crystal structure and hydrophobic nature of the two forms.
Pharmacodynamic studies on the same subjects showed an increase of intragastric pH with tenatoprazole 40 mg daily for seven days, significantly higher (p<0.05) than that observed with the same regimen of esomeprazole, the median pH being 4.6±0.9 and 4.2±0.8, respectively. In addition, the time spent above pH 4 at night after tenatoprazole administration was significantly longer than that observed with esomeprazole. The intragastric pH during the night was similarly higher (4.7±1.1 Units with tenatoprazole and 3.6±1.4 Units with esomeprazole, p<0.01), indicating better acid control.
A more recent pharmacodynamic and pharmacokinetic investigation did confirm and extended previous data showing the prolonged duration of acid suppression with tenatoprazole. The proportion of healthy volunteers spending at least 16 h above pH 4 in the 24 h period was remarkably higher with tenatoprazole than with esomeprazole (81.5% versus 34.5%, p<0.001) while the proportion of subjects with NAB was lower (73.1% versus 93.1%, p=0.06), although the difference fell short of statistical significance. Even 3 days after treatment was discontinued, mean 24 h pH, and percentage of time at pH>3 and pH>4 were significantly higher with tenatoprazole, indicating a sustained control of intragastric acidity with this novel PPI compared to esomeprazole. After 7 days repeated dosing, the maximal plasma concentration of tenatoprazole was almost six times higher than that of esomeprazole while AUC was 32 times higher. A significant correlation between AUC and percentage of time intragastric pH>4 was observed with tenatoprazole not only during but also after stopping treatment.
In summary, available studies point out both pharmacokinetic and pharmacodynamic advantages of tenatoprazole over esomeprazole. Since this last compound provides – amongst the members of the class — the most effective control of intragastric pH whatever the parameter considered, it is conceivable that tenatoprazole could similarly be better than the other existing PPIs. Tenatoprazole (as well as its S-isomer) appears a promising PPI for the treatment of acid-related diseases, where it has the potential to address unmet clinical needs.