Stereoselective Disposition of Proton??Pump Inhibitors

Clinical Pharmacology and DMPK, AstraZeneca R&D Mölndal, Mölndal, Sweden.
Clinical Drug Investigation (Impact Factor: 1.56). 02/2008; 28(5):263-79. DOI: 10.2165/00044011-200828050-00001
Source: PubMed


It is estimated that about half of all therapeutic agents are chiral, but most of these drugs are administered in the form of the racemic mixture, i.e. a 50/50 mixture of its enantiomers. However, chirality is one of the main features of biology, and many of the processes essential for life are stereoselective, implying that two enantiomers may work differently from each other in a physiological environment. Thus, receptors or metabolizing enzymes would recognize one of the ligand enantiomers in favour of the other. With one exception, all presently marketed proton pump inhibitors (PPIs)--omeprazole, lansoprazole, pantoprazole and rabeprazole--used for the treatment of gastric acid-related diseases are racemic mixtures. The exception is esomeprazole, the S-enantiomer of omeprazole, which is the only PPI developed as a single enantiomer drug. The development of esomeprazole (an alkaline salt thereof, e.g. magnesium or sodium) was based on unique metabolic properties that clearly differentiated esomeprazole from omeprazole, the racemate. At comparable doses, these properties led to several clinical advantages, for example higher bioavailability in the majority of patients, i.e. the extensive metabolizers (EMs; 97% in Caucasian and 80-85% in Asian populations), lower exposure in poor metabolizers (PMs; 3% in Caucasian and 15-20% in Asian populations) and lower interindividual variation. For the other, i.e. racemic, PPIs there are some data available on the characteristics of the individual enantiomers, and we have therefore undertaken to analyse the current literature with the purpose of evaluating the potential benefits of developing single enantiomer drugs from lansoprazole, pantoprazole and rabeprazole. For lansoprazole, the plasma concentrations of the S-enantiomer are lower than those of the R-enantiomer in both EMs and PMs, and, consequently, the variability in the population or between EMs and PMs is not likely to decrease with either of the lansoprazole enantiomers. Furthermore, plasma protein binding differs between the two lansoprazole enantiomers, in that the amount of the free S-enantiomer is two-fold higher than that of the R-enantiomer. This will counteract the difference seen in total plasma concentrations of the enantiomers. Also, studies using expressed human cytochrome P450 isoenzymes show that the metabolism of one enantiomer is significantly affected by the presence of the other, which is likely to result in different pharmacokinetics when administering a single enantiomer. For pantoprazole, there is a negligible difference in plasma concentrations between the two enantiomers in EMs, while the difference is substantial in PMs. The difference in AUC between PMs and EMs would decrease to some extent, but in the majority of the population the variability and efficacy would not be altered with a single enantiomer of pantoprazole. The metabolism of the enantiomers of rabeprazole displays stereoselectivity comparable to that of lansoprazole, i.e. the exposure of the R-enantiomer is higher than that of the S-enantiomer in EMs as well as in PMs, which, by analogy to lansoprazole, makes them less suitable for development of a single enantiomer drug. Furthermore, the chiral stability of the rabeprazole enantiomers may be an issue because of significant degradation of rabeprazole to its sulfide analogue, which is subject to non-stereoselective metabolic regeneration of a mixture of the two enantiomers. In conclusion, in contrast to esomeprazole, the S-enantiomer of omeprazole, minimal if any clinical advantages would be expected in developing any of the enantiomers of lansoprazole, pantoprazole, or rabeprazole as compared with their racemates.

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    • "Both compounds contain the asymmetric chiral sulfur atom in their chemical structure and therefore they exist in form R- and S-enantiomers. Enantiopure drug Esomeprazole (S-OME), having improved metabolic properties, such as higher bioavailability and lower inter-individual variation as compared to racemic drug was developed in 2001 [1]–[3]. FDA has approved Dexlansoprazole (R-LAN) in 2009 as an enatiopure drug for treatment of gastro esophageal reflux disease [4], [5]. "
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    ABSTRACT: Benzimidazole drugs lansoprazole and omeprazole are used for treatment of various gastrointestinal pathologies. Both compounds cause drug-drug interactions because they activate aryl hydrocarbon receptor and induce CYP1A genes. In the current paper, we examined the effects of lansoprazole and omeprazole enantiomers on the expression of key drug-metabolizing enzyme CYP3A4 in human hepatocytes and human cancer cell lines. Lansoprazole enantiomers, but not omeprazole, were equipotent inducers of CYP3A4 mRNA in HepG2 cells. All forms (S-, R-, rac-) of lansoprazole and omeprazole induced CYP3A4 mRNA and protein in human hepatocytes. The quantitative profiles of CYP3A4 induction by individual forms of lansoprazole and omeprazole exerted enantiospecific patterns. Lansoprazole dose-dependently activated pregnane X receptor PXR in gene reporter assays, and slightly modulated rifampicin-inducible PXR activity, with similar potency for each enantiomer. Omeprazole dose-dependently activated PXR and inhibited rifampicin-inducible PXR activity. The effects of S-omeprazole were much stronger as compared to those of R-omeprazole. All forms of lansoprazole, but not omeprazole, slightly activated glucocorticoid receptor and augmented dexamethasone-induced GR transcriptional activity. Omeprazole and lansoprazole influenced basal and ligand inducible expression of tyrosine aminotransferase, a GR-target gene, in HepG2 cells and human hepatocytes. Overall, we demonstrate here that omeprazole and lansoprazole enantiomers induce CYP3A4 in HepG2 cells and human hepatocytes. The induction comprises differential interactions of omeprazole and lansoprazole with transcriptional regulators PXR and GR, and some of the effects were enantiospecific. The data presented here might be of toxicological and clinical importance, since the effects occurred in therapeutically relevant concentrations.
    PLoS ONE 08/2014; 9(8):e105580. DOI:10.1371/journal.pone.0105580 · 3.23 Impact Factor
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    • "However there are quantitative differences in stereoselective metabolism by human CYPs. Lansoprazole stereoselectivity seems to be mainly based on CYP3A4 selectivity in preference for the S-enantiomer, whereas for omeprazole stereoselectivity is based on both CYP3A4 preference for the S-enantiomer and CYP2C19 preference for the R-enantiomer [5], [8], [12]. In addition, omeprazole and lansoprazole have been shown to induce CYP1A genes in human hepatoma cells and primary human hepatocytes [13]–[15]. "
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    ABSTRACT: Proton pump inhibitors omeprazole and lansoprazole contain chiral sulfur atom and they are administered as a racemate, i.e. equimolar mixture of S- and R-enantiomers. The enantiopure drugs esomeprazole and dexlansoprazole have been developed and introduced to clinical practice due to their improved clinical and therapeutic properties. Since omeprazole and lansoprazole are activators of aryl hydrocarbon receptor (AhR) and inducers of CYP1A genes, we examined their enantiospecific effects on AhR-CYP1A pathway in human cancer cells and primary human hepatocytes. We performed gene reporter assays for transcriptional activity of AhR, RT-PCR analyses for CYP1A1/2 mRNAs, western blots for CYP1A1/2 proteins and EROD assay for CYP1A1/2 catalytic activity. Lansoprazole and omeprazole enantiomers displayed differential effects on AhR-CYP1A1/2 pathway. In general, S-enantiomers were stronger activators of AhR and inducers of CYP1A genes as compared to R-enantiomers in lower concentrations, i.e. 1-10 µM for lansoprazole and 10-100 µM for omeprazole. In contrast, R-enantiomers were stronger AhR activators and CYP1A inducers than S-enantiomers in higher concentrations, i.e. 100 µM for lansoprazole and 250 µM for omeprazole. In conclusion, we provide the first evidence of enantiospecific effects of omeprazole and lansoprazole on AhR signaling pathway.
    PLoS ONE 06/2014; 9(6):e98711. DOI:10.1371/journal.pone.0098711 · 3.23 Impact Factor
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    • "Therefore, the aim of the present study was to assess the steady-state pharmacokinetic interaction between lesogaberan and esomeprazole when administered alone and concomitantly to healthy subjects. Esomeprazole was chosen to represent the PPIs as a class because it is widely prescribed and mainly metabolized by cytochrome P450 (CYP) 2C19 and CYP3A4,[5] as with omeprazole,[6,7] lansoprazole,[8,9] pantoprazole,[6,10] and rabeprazole.[11,12] "
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    ABSTRACT: Transient lower esophageal sphincter relaxations (TLESRs) have been identified as a primary cause of reflux events in patients with gastroesophageal reflux disease (GERD). GABA(B) receptor agonists such as lesogaberan (AZD3355) have been shown to inhibit TLESRs in healthy subjects and patients with GERD, and, therefore, offer a novel therapeutic add-on strategy to acid suppression for the management of GERD. As lesogaberan is being developed as an add-on treatment for the management of patients with GERD who have a partial response to proton pump inhibitor (PPI) therapy, it is important to rule out any clinically important pharmacokinetic drug-drug interaction between lesogaberan and PPIs. To evaluate the effect of esomeprazole on the pharmacokinetics and safety of lesogaberan and vice versa. This was an open-label, randomized, three-way crossover study. The study was open to healthy adult male and female subjects. The study subjects received treatment with, in random order, lesogaberan (150 mg twice daily [dose interval 12 hours]), esomeprazole (40 mg once daily), and a combination of both, during 7-day treatment periods. The presence or absence of pharmacokinetic interactions between lesogaberan and esomeprazole was assessed by measuring the steady-state area under the plasma concentration-time curves during the dosing interval (AUC(τ)) and the maximum observed plasma concentration (C(max)) for lesogaberan and esomeprazole. Thirty male subjects (mean age 23.2 years, 97% Caucasian) were randomized to treatment and 28 subjects completed the study (one subject was lost to follow-up, and one subject discontinued due to an adverse event). The 95% confidence intervals of the geometric mean ratios for AUC(τ) and C(max) of lesogaberan and esomeprazole administered alone and concomitantly were within the recognized boundaries of bioequivalence (0.8-1.25). No new safety concerns were raised during this study. The number of patients with adverse events during treatment with lesogaberan alone (n = 17) and concomitantly with esomeprazole (n = 18) were comparable but higher than with esomeprazole alone (n = 10). Paresthesia (episodic, mild, and transient), pharyngitis, and flatulence were the most frequently reported adverse events. There was no observed pharmacokinetic interaction between lesogaberan and esomeprazole when concomitantly administered to healthy subjects, and concomitant therapy was well tolerated. TRIAL REGISTRATION NUMBER ( NCT00684190.
    11/2010; 10(4):243-51. DOI:10.2165/11588180-000000000-00000
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