Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects

Hassan-Alin, Mohammed; Röhss, Kerstin; Andersson, Tommy; Nyman, Lars

doi:10.1016/s0016-5085(00)82133-2

Cited by 49 publications

(66 citation statements)

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“…For the individual incubation of S-OME in HLM, however, the relative formation rate of 5-OH-OME to that of the sulfone did not change significantly with increasing S-OME concentration. The sulfone is the major metabolite formed, with concentrations approximately 2-fold higher than those of 5-OH-OME in the S-OME range from 1 to 100 M. This result is in good agreement with an in vivo study, where the plasma concentration (C max ) of OME sulfone was approximately 2.5-fold that of 5-OH-OME after a single oral dose of 40 mg of esomeprazole (Hassan-Alin et al, 2000). This finding suggests that the metabolism of S-OME is less dependent on CYP2C19.…”

Section: Enantiomer Interactions Of S-and R-omeprazole On P450s 785supporting

confidence: 88%

Enantiomer/Enantiomer Interactions between theS- andR- Isomers of Omeprazole in Human Cytochrome P450 Enzymes: Major Role of CYP2C19 and CYP3A4

Li¹,

Weidolf²,

Simonsson³

et al. 2005

J Pharmacol Exp Ther

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We investigated the enzyme kinetic basis for the stereoselective disposition of R-and S-omeprazole (OME) and racemic OME in human liver microsomes. OME is primarily metabolized by the hepatic cytochrome P450 enzyme system (CYP2C19 and 3A4). The metabolism of each enantiomer and pseudoracemic OME was studied using unlabeled and 13 C 7 -labeled enantiomers. The enantiomers inhibited each other's metabolism competitively in human liver microsomes and in recombinant CYP2C19 and 3A4. The results obtained with the individual enantiomers allowed successful prediction of the enzyme kinetics for the pseudoracemate. The intrinsic clearance of each enantiomer in a pseudoracemic mixture remained the same as those of the individually incubated enantiomers, although K m and V max decreased. In the pseudoracemate, the relative contribution of CYP2C19 and 3A4 to 5-hydroxylation and 5Ј-O-demethylation of R-OME was comparable to that obtained for the incubation of R-OME alone. For S-OME, however, the presence of its antipode greatly increased the contribution of CYP3A4, with increasing concentrations, compared with that obtained when incubating S-OME alone. The results of our in vitro study clearly show metabolic interactions between the OME enantiomers, which may also occur in vivo. Because the enantiomers of OME produce similar pharmacological effects, the enantiomer interactions should not significantly affect the pharmacodynamics. On the other hand, the use of the S-enantiomer results in less complex enzyme kinetics than those of the racemate; thus, the outcome of its clinical use is more predictable.Omeprazole (OME), a proton pump inhibitor (PPI), has been widely used for many years as an acid inhibitory agent for the treatment of gastric acid hypersecretion disorders. OME is a chiral compound and the sulfinyl group is the chiral center (Fig. 1). It is administered as a racemic (50/50) mixture of the S-and R-enantiomers. Recently, its optical Sisomer has been developed as a new drug (esomeprazole). OME as well as its enantiomers are prodrugs with a common mechanism of action involving chemical rearrangement to a pharmacologically active achiral sulfenamide in the acidic compartment of parietal cells (Lindberg et al., 1986). The formed sulfenamide reacts with sulfhydryl groups of the enzyme H ϩ ,K ϩ -ATPase (the proton pump), which is located in the canaliculi of the parietal cells, thus inhibiting its ability to participate in gastric acid formation. OME and its enantiomers are thus equally potent H ϩ ,K ϩ -ATPase inhibitors (Andersson et al., 2001). However, R-and S-OME show stereoselective disposition because of the enzyme-catalyzed stereoselective metabolism that leads to the higher metabolic stability of esomeprazole compared with its R-isomer and the racemate, which has been demonstrated in vitro using human liver microsomes (Äbelö et al., 2000). The resulting increase in drug exposure in the majority of the population, as indicated by the higher area under the plasma concentration-time curve after esomeprazole ...

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Section: Enantiomer Interactions Of S-and R-omeprazole On P450s 785supporting

confidence: 88%

Enantiomer/Enantiomer Interactions between theS- andR- Isomers of Omeprazole in Human Cytochrome P450 Enzymes: Major Role of CYP2C19 and CYP3A4

Li¹,

Weidolf²,

Simonsson³

et al. 2005

J Pharmacol Exp Ther

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“…7 Esomeprazole is the S-isomer of omeprazole and the first PPI developed as a single isomer. Esomeprazole has an enhanced pharmacodynamic and pharmacokinetic profile resulting in more effective and longer-lasting inhibition of gastric acid secretion over the 24-hour dosing period [8][9][10] and is more effective at healing and resolution of heartburn than the racemic omeprazole. [11][12][13] Intragastric acid is more effectively controlled with the standard dose of esomeprazole (40 mg once daily) than standard doses of all other PPIs, as measured by the percentage of time pH > 4.0 and mean 24-hour pH.…”

Section: Introductionmentioning

confidence: 99%

A comparison of esomeprazole and lansoprazole for control of intragastric pH in patients with symptoms of gastro‐oesophageal reflux disease

Johnson

Stacy

Ryan

et al. 2005

Aliment Pharmacol Ther

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SUMMARYBackground: Intragastric acid suppression is the most direct measure of the pharmacodynamic efficacy of proton pump inhibitors, which are the most effective drugs for acid-related diseases. Aim: To compare the effectiveness of once and twice daily dosing of lansoprazole and esomeprazole in controlling intragastric acidity (target gastric pH > 4.0) over a 24-hour period. Methods:In an open-label, two-way crossover study, 45 Helicobacter pylori-negative patients with gastro-oesophageal reflux disease were randomized to receive one of two regimens: 30 mg lansoprazole or esomeprazole 40 mg once daily. Intragastric pH was assessed by 24-hour pH monitoring on day 5 of each regimen. Dosing was increased to twice daily and pH was reassessed on day 10. Following a 14-day washout, patients were crossed over to the other medication and the dosage regimens and pH assessments were repeated.

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“…They allow quick symptom resolution and high healing rates of mucosal breaks (4,5,8) . Esomeprazole, an S isomer of omeprazole, is a step ahead in relation to previous PPIs, and has a smaller first pass hepatic metabolism and a reduced systemic clearance, with a higher and more persistent plasmatic concentration (11) . This increase in bioavailability results in a more intense and more prolonged suppression of gastric acidity, offering a perspective of greater efficacy in the treatment of acid related diseases (16) , particularly GERD.…”

Section: Discussionmentioning

confidence: 99%

Clinical and endoscopic evaluantion of gastroesophageal reflux disease in patients successfully treated with esomeprazole

Silva

Nader

Quilici

et al. 2003

Arq. Gastroenterol.

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-Background -Esomeprazole, an S-isomer of omeprazole, is the first proton pump inhibitor developed as an optical isomer, and it has shown high healing rates in erosive esophagitis. Aim -To evaluate the efficacy and tolerability of esomeprazole in subjects with erosive esophagitis, according to the Los Angeles classification study design: an open, multi-center clinical study. Material and Methods -Two hundred and eighteen subjects with reflux esophagitis confirmed by endoscopy were included in an open, multi-center study in Brazil. All of them received esomeprazole 40 mg, once daily, for a 4-week period. Subjects who had unhealed esophagitis by week 4 continued the treatment for another 4 weeks. The primary efficacy endpoint was the healing rates by weeks 4 and 8. The secondary endpoints were the number of patients with symptom resolution by week 4, the number of days to sustained symptom resolution, number of symptom-free days and nights and safety and tolerability of the drug. Results -Healing rates by weeks 4 and 8 were 82% (confidence interval: 77.4%-87.6%) and 96.1% (confidence interval: 93.5% -98.8%), respectively. Ninety-nine (99%) of the patients had heartburn resolution by week 2. The most common adverse events were headache (4%), diarrhea (2.6%) and epigastric pain (2.2%). Conclusion -For the studied period, esomeprazole was shown to be a safe and well-tolerated drug, providing significant healing rates of mucosal breaks, regardless of LA classification, in patients with erosive esophagitis. Esomeprazole was also shown to be effective in quickly relieving symptoms.

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Pharmacokinetics of esomeprazole after oral and intravenous administration of single and repeated doses to healthy subjects

Cited by 49 publications

References 0 publications

Enantiomer/Enantiomer Interactions between theS- andR- Isomers of Omeprazole in Human Cytochrome P450 Enzymes: Major Role of CYP2C19 and CYP3A4

Enantiomer/Enantiomer Interactions between theS- andR- Isomers of Omeprazole in Human Cytochrome P450 Enzymes: Major Role of CYP2C19 and CYP3A4

A comparison of esomeprazole and lansoprazole for control of intragastric pH in patients with symptoms of gastro‐oesophageal reflux disease

Clinical and endoscopic evaluantion of gastroesophageal reflux disease in patients successfully treated with esomeprazole

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