Introduction

Esomeprazole magnesium trihydrate, is a classical example of proton pump inhibitors and is approved by FDA for the treatment of symptomatic gastro esophageal reflux disease, short-term treatment and maintenance of erosive esophagitis. Esomeprazole magnesium trihydrate is a white to slightly colored powder (Figure 1). The solubility of esomeprazole magnesium trihydrate in water is approximately 1.5mg/ml,with a corresponding pH of 10.0. Esomeprazole is an S-isomer of omeprazole and the first proton pump inhibitor to be developed as an optical isomer [1]. The drug has an improved pharmacokinetic pro?le, resulting in increased systemic exposure and less inter individual variability compared with omeprazole, and more effective suppression of gastric acid production compared with other proton pump inhibitors.[2]

Synthesis of esomeprazole magnesium trihydrate

Methods: Esomeprazole magnesium trihydrate was prepared by condensation,sharpless asymmetric oxidation,salt,ion exchange and crystal transformation with 2-mercapto-5-methoxy-benzimidazole and 2-chloromethyl-3, 5-dimethyl-4-methoxypyridine hydrochloride as the starting materials. Results: 46.2 kg white crystal esomeprazole magnesium trihydrate which was in line with the pharmaceutically acceptable form was obtained by the technology.The total molar yield was 64.7%,the chromatographic purity was 99.9%,and ee was 100%.Conclusion: The synthesis process is simple and easy to operate with a high yield which can meet the requirements of medicine for industrial production need.[3]

Pharmacology/mechanism of action

Esomeprazole magnesium trihydrate, as other PPIs, reduces gastric acid secretion by inhibiting the H+/K+-adenosine triphosphatase enzyme, which is the proton pump in gastric parietal cells. Esomeprazole magnesium trihydrate penetrates the parietal cells and as a weak base in this acidic environment, it undergoes protonation and conversion to achiral sulfenamide, the active drug, which reacts with select cysteines to inhibit the proton pump. The relative potency of PPIs have primarily focused on the inhibition of the proton pump in reducing intra-gastric secretion and on the inhibiting effect on the cytochrome P450 system.[4]

Hellstr?m and Vitols reviewed relative anti-secretory potency of PPIs, including lansoprazole, omeprazole, pantoprazole, rabeprazole and esomeprazole, demonstrating that lansoprazole, omeprazole, pantoprazole and rabeprazole have similar potency on a milligram to milligram basis. Esomprazole magnesium trihydrate at 40 mg/day showed greater gastric acid inhibitory potency than other PPIs with doses of omeprazole: 40 mg/day, lansoprazole: 30 mg/day, pantoprazole: 40 mg/day and rabeprazole: 20 mg/day. Rabeprazole exhibited a slightly more rapid onset of activity.[5]

Pharmacokinetic characteristics

The pharmacokinetics of esomeprazole magnesium trihydrate has been evaluated in both healthy volunteers and GERD patients, including pediatric and adult populations. The absorption distribution and elimination pharmacokinetics of esomeprazole magnesium trihydrate are reviewed. The clinical application of the pharmacokinetic parameters herein presented provides rationale for dosing regimens and optimal administration direction. The absorption pharmacokinetic parameters of Cmax and tmax provide information on the onset and height of activity. The bioavailability (F) demonstrates the extent of absorption which governs the amount of drug available for systemic effects. AUC is a component of F and kinetically demonstrates plasma concentration over time. The elimination parameters of half-life (t1/2) and clearance (CL) demonstrate how a drug is cleared from the body. Plasma t1/2 may vary from biologic half-life in certain drug entities; PPIs are included in this category. Clearance is a parameter that more accurately reflects drug elimination because it incorporates the distribution parameters of volume of distribution. This latter parameter also takes into account protein binding and other factors involved with systemic availability and subsequent drug receptor effect. Pharmacokinetic parameters of esomeprazole magnesium trihydrateare also determined for both single dose and chronic repetitive dosing studies with the latter reflecting steady-state conditions with final chronic dosing clinical effects. [4]

Table 1 displays the pharmacokinetic parameters of esomeprazole in both adults and pediatric patients.

Metabolism

Esomeprazole magnesium trihydrate is extensively metabolized in the liver by the cytochrome P450 (CYP) enzyme system. The metabolites of esomeprazole magnesium trihydrate lack antisecretory activity. The major part of esomeprazole’s metabolism is dependent upon the CYP2C19 isoenzyme, which forms the hydroxy and desmethyl metabolites. The remaining amount is dependent on CYP3A4 which forms the sulphone metabolite. CYP2C19 isoenzyme exhibits polymorphism in the metabolism of esomeprazole magnesium trihydrate, since some 3% of Caucasians and 15 to 20% of Asians lack CYP2C19 and are termed Poor Metabolizers. However, the influence of CYP 2C19 polymorphism is less pronounced for esomeprazole magnesium trihydrate than for omeprazole.[6] At steady state, the ratio of AUC in Poor Metabolizers to AUC in the rest of the population (Extensive Metabolizers) is approximately 2.

Following administration of equimolar doses, the S- and R-isomers are metabolized differently by the liver, resulting in higher plasma levels of the S- than of the R-isomer.

Nine major urinary metabolites of esomeprazole magnesium trihydratehave been detected. The two main metabolites have been identified as hydroxyesomeprazole and the corresponding carboxylic acid. Three major metabolites of  esomeprazole magnesium trihydrate have been identified in plasma: the 5-O-desmethyl- and sulphone derivatives and hydroxyesomeprazole. The major metabolites of esomeprazole have no effect on gastric acid secretion.[6]

References

[1] Johnson DA. Review of esomeprazole in the treatment of acid disorders. Expert Opin Pharmacotherapy. 2003; 4: 253-264.

[2] Nair AB, Gupta R, Kumria R, Jacob S, Attimarad M. Formulation and evaluation of enteric coated tablets of proton pump inhibitor. J Basic Clin Pharm. 2010;1(4):215-221.

[3] Yangyang C , Jingan X , Fengquan Y ,et al.New production technology of esomeprazole magnesium trihydrate[J].Journal of Guangdong Pharmaceutical University, 2016; 32(4): 436-438.

[4] Saccar CL. The pharmacology of esomeprazole and its role in gastric acid related diseases. Expert Opin Drug Metab Toxicol. 2009;5(9):1113-1124.

[5] Hellstr?m PM, Vitols S. The choice of proton pump inhibitor: does it matter? Clin Pharmacol Toxicol 2004;94:106-11

[6] Esomeprazole: Uses, Interactions, Mechanism of Action | DrugBank Online  https://go.drugbank.com/drugs/DB00736