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General Description:

Dexlansoprazole, identified by CAS number 138530-94-6, is a notable compound with significant therapeutic applications. Dexlansoprazole is a new generation proton pump inhibitor (PPI) used for the management of symptoms associated with gastroesophageal reflux disease (GERD) and erosive esophagitis. Dexlansoprazole is the R-enantiomer of , which is composed of a racemic mixture of the R- and S-enantiomers. Compared to the older generation of PPIs (which includes , , and ) , dexlansoprazole MR has a unique pharmacokinetic profile due to its delayed-release and dual-delivery release system. The active ingredient is released in two phases at different pH values and at different time points, resulting in two peak concentrations in the blood; 25% of the dose is released at pH 5.5 in the proximal duodenum, while the remaining 75% is released at pH 6.75 in the distal small intestine . As a result, dexlansoprazole has a peak concentration within 1-2 hours after dosing and another within 4-5 hours . Dexlansoprazole's unique pharmacokinetics addresses limitations of the older generation PPIs including short plasma half-life, break-through symptoms, and need for meal-associated dosing . These characteristics make dexlansoprazole a good option for people who struggle with adherence and strict dosage timing before meals. Dexlansoprazole exerts its stomach acid-suppressing effects in the same way as other drugs in the PPI family by inhibiting the final step in gastric acid production. Dexlansoprazole targets the (H+, K+)-ATPase enzyme, which is involved in the secretion of hydrochloric acid through the exchange of H+ ions from the cytoplasm for K+ ions. Normally functioning (H+, K+)-ATPase stimulates hydrochloric acid secretion into the gastric lumen thereby increasing stomach acidity and lowering pH. Once absorbed into circulation, dexlansoprazole covalently binds to the sulfhydryl groups of cysteines found on the (H+, K+)-ATPase enzyme at the secretory surface of gastric parietal cells, which leads to inhibition of both basal and stimulated gastric acid secretion. Despite dexlansoprazole's unique pharmacokinetic profile, efficacy in management of GERD symptoms is considered similar to other medications within the PPI class including , , , , and . Due to their good safety profile and as several PPIs are available over the counter without a prescription, their current use in North America is widespread. Long term use of PPIs such as dexlansoprazole have been associated with possible adverse effects, however, including increased susceptibility to bacterial infections (including gastrointestinal _C. difficile_), reduced absorption of micronutrients including iron and B12, and an increased risk of developing hypomagnesemia and hypocalcemia which may contribute to osteoporosis and bone fractures later in life . PPIs such as dexlansoprazole have also been shown to inhibit the activity of dimethylarginine dimethylaminohydrolase (DDAH), an enzyme necessary for cardiovascular health. DDAH inhibition causes a consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), which is thought to cause the association of PPIs with increased risk of cardiovascular events in patients with unstable coronary syndromes . Dexlansoprazole doses should be slowly lowered, or tapered, before discontinuing as rapid discontinuation of PPIs such as dexlansoprazole may cause a rebound effect and a short term increase in hypersecretion .

Indications:

This drug is primarily indicated for: Dexlansoprazole is indicated for healing all grades of erosive esophagitis (EE), maintaining and healing of EE and relief of heartburn, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Dexlansoprazole undergoes metabolic processing primarily in: Dexlansoprazole is extensively metabolized in the liver by oxidation, reduction, and subsequent formation of sulfate, glucuronide and glutathione conjugates to inactive metabolites. Oxidative metabolites are formed by the cytochrome P450 (CYP) enzyme system including hydroxylation mainly by CYP2C19, and oxidation to the sulfone by CYP3A4. Dexlansoprazole is the major circulating component in plasma regardless of CYP2C19 metabolizer status. In CYP2C19 intermediate and extensive metabolizers, the major plasma metabolites are 5-hydroxy dexlansoprazole and its glucuronide conjugate, while in CYP2C19 poor metabolizers dexlansoprazole sulfone is the major plasma metabolite. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Dexlansoprazole are crucial for its therapeutic efficacy: After oral administration, the peak plasma concentration increases approximately dose proportionally. The dual delayed release formulation achieves two plasma concentration peaks, where the first peak occurs one to two hours after administration, followed by a second peak within four to five hours. The delivery technology of dexlansoprazole MR is designed to release the drug in two separate pH-dependent phases, the first in the proximal duodenum (25% of total drug dose) and the second (75% of total drug dose) in the more distal small intestine. The median time (Tmax) to peak plasma concentrations (Cmax) of 30 mg dexlansoprazole was 4 hours and ranged from 1 to 6 hours with the Cmax value of 688 ng/mL. AUC was found to be 3275 (ng∙h/mL). The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Dexlansoprazole is an important consideration for its dosing schedule: Dexlansoprazole is eliminated with a half-life of approximately one to two hours in healthy subjects and in patients with symptomatic GERD. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Dexlansoprazole exhibits a strong affinity for binding with plasma proteins: Plasma protein binding of dexlansoprazole ranged from 96% to 99% in healthy subjects and was independent of concentration from 0.01 to 20 mcg/mL . This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Dexlansoprazole from the body primarily occurs through: Dexlansoprazole is cleared from the body by either fecal excretion (50.7%) or renal excretion (47.6%) following oral ingestion, with no unchanged drug detected in the urine. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Dexlansoprazole is distributed throughout the body with a volume of distribution of: The apparent volume of distribution after multiple doses in symptomatic GERD patients was 40.3 L . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Dexlansoprazole is a critical factor in determining its safe and effective dosage: Apparent clearance (CL/F) in healthy subjects was 11.4 to 11.6 L/hour, respectively, after five days of 30 or 60 mg once daily administration. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Dexlansoprazole exerts its therapeutic effects through: Dexlansoprazole is a proton pump inhibitor (PPI) and is included in the drug class of antisecretory compounds. It blocks the final step of gastric acid secretion by specific inhibition of the (H+, K+)-ATPase at the secretory surface of the parietal cells on gastric mucosa. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Dexlansoprazole functions by: Dexlansoprazole inhibits the H/K ATPase enzyme, which is involved in the secretion of hydrochloric acid, hydrolyzing ATP and exchanging H+ ions from the cytoplasm for K+ ions in the secretory canaliculus, which results in HCl secretion into the gastric lumen. Dexlansoprazole inhibits this effect of H/K ATPase by demonstrating a high degree of activation in the acidic environment. After passing through the liver and reaching the gastric parietal cells activated by a meal, PPIs undergo protonation in the acidic pH environment, followed by conversion to sulphenamide which represents the active form of the drug. Sulphenamide inhibits the activity of the proton pump and hence the transport of hydrogen ions into the gastric lumen via covalent binding to the SH groups of the cysteine residues of H/K ATPase . The delivery technology of dexlansoprazole MR is designed to release the drug in two separate pH-dependent phases, the first in the proximal duodenum (25% of total drug dose) and the second (75% of total drug dose) in the more distal small intestine. Dexlansoprazole reduces both basal and stimulated gastric acid secretion. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Dexlansoprazole belongs to the class of organic compounds known as sulfinylbenzimidazoles. These are polycyclic aromatic compounds containing a sulfinyl group attached at the position 2 of a benzimidazole moiety, classified under the direct parent group Sulfinylbenzimidazoles. This compound is a part of the Organic compounds, falling under the Organoheterocyclic compounds superclass, and categorized within the Benzimidazoles class, specifically within the Sulfinylbenzimidazoles subclass.

Categories:

Dexlansoprazole is categorized under the following therapeutic classes: 2-Pyridinylmethylsulfinylbenzimidazoles, Acid Reducers, Alimentary Tract and Metabolism, Anti-Ulcer Agents, Benzimidazoles, Cytochrome P-450 CYP2C19 Inhibitors, Cytochrome P-450 CYP2C19 Inhibitors (weak), Cytochrome P-450 CYP2C19 Substrates, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Substrates, Drugs for Acid Related Disorders, Drugs for Peptic Ulcer and Gastro-Oesophageal Reflux Disease (Gord), Enzyme Inhibitors, Gastric Acid Lowering Agents, Gastrointestinal Agents, Heterocyclic Compounds, Fused-Ring, Proton Pump Inhibitors, Proton-pump Inhibitors, Pyridines, Sulfoxides, Sulfur Compounds. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Dexlansoprazole include:

• Water Solubility: 0.21mg/mL at pH7.0
• Melting Point: Decomposes at 140ºC
• logP: 2.38
• pKa: 8.87