Abstract
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.
Similar content being viewed by others
References
Agranat I, Caner H, Caldwell J. Putting chirality to work: the strategy of chiral switches. Nat Rev Drug Discov 2002; 1: 753–68
Creutzfeldt W. Chiral switch, a successful way for developing drugs: example of esomeprazole [in German]. Z Gastroenterol 2000; 38(11): 893–7
Andersson, T. Single-isomer drugs: true therapeutic advances. Clin Pharmacokinet 2004; 43: 279–85
Abelö A, Andersson TB, Antonsson M, et al. Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab Dispos 2000; 28: 966–72
Andersson T, Hassan-Alin M, Hasselgren G, et al. Pharmacokinetic studies with esomeprazole, the (S)-isomer of omeprazole. Clin Pharmacokinet 2001; 40: 411–26
Röhss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastro-oesophageal reflux symptoms. Eur J Clin Pharmacol 2004; 60: 531–9
Miner Jr P, Katz PO, Chen Y, et al. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterol 2003; 98: 2616–20
Hassan-Alin M, Andersson T, Niazi M, et al. A pharmacokinetic study comparing single and repeated oral doses of 20 and 40mg omeprazole and its two optical isomers, S-omeprazole (esomeprazole) and R-omeprazole, in healthy subjects. Eur J Clin Pharmacol 2005; 60: 779–84
Katsuki H, Hamada A, Nakamura C, et al. Role of CYP3A4 and CYP2C19 in the stereoselective metabolism of lansoprazole by human liver microsomes. Eur J Clin Pharmacol 2001; 57: 709–15
Kim KA, Kim MJ, Park YU, et al. Stereoselective metabolism of lansoprazole by human liver cytochromes P450 enzymes. Drug Metab Dispos 2003; 31: 1227–34
Katsuki H, Yagi H, Arimori K, et al. Determination of R(+)- and S(−)-lansoprazole using chiral stationary-phase liquid chromatography and their enantioselective pharmacokinetics in humans. Pharm Res 1996; 13: 611–5
Kim KA, Shon JH, Park JY, et al. Enantioselective disposition of lansoprazole in extensive and poor metabolizers of CYP2C19. Clin Pharmacol Ther 2002; 72: 90–9
Miura M, Tada H, Suzuki T, et al. Simultaneous determination of lansoprazole enantiomers and their metabolites in plasma by liquid chromatography with solid phase extraction. J Chromatogr B 2004; 804: 389–95
Miura M, Tada H, Yasui-Furukori N, et al. Pharmacokinetic differences between the enantiomers of lansoprazole and its metabolite, 5-hydroxylansoprazole, in relation to CYP2C19 genotypes. Eur J Clin Pharmacol 2004; 60: 623–8
Miura M, Kagaya H, Tada H, et al. Comparison of enantioselective disposition of rabeprazole versus lansoprazole in renaltransplant recipients who are CYP2C19 extensive metabolizers. Xenobiotica 2005; 35: 479–86
Tanaka M, Yamazaki H, Hakusui H, et al. Differential stereo-selective pharmacokinetics of pantoprazole, a proton pump inhibitor in extensive and poor metabolizers of pantoprazole: a preliminary study. Chirality 1997; 9: 17–21
Tanaka M, Ohkubo T, Otani K, et al. Stereoselective pharmacokinetics of pantoprazole, a proton pump inhibitor, in extensive and poor metabolizers of S-mephenytoin. Clin Pharmacol Ther 2001; 69: 108–13
Cass QB, Degani ALG, Cassiano NM, et al. Enantiomeric determination of pantoprazole in human plasma by multidimensional high-performance liquid chromatography. J Chromatogr B 2001; 766: 153–60
Miura M, Kagaya H, Tada H, et al. Enantioselective disposition of rabeprazole in relation to CYP2C19 genotypes. Br J Clin Pharmacol 2005; 61: 315–20
Lindberg P, Brändstrom A, Wallmark B, et al. Omeprazole: the first proton pump inhibitor. Med Res Rev 1990; 10: 1–54
Lind T, Cederberg C, Ekenved G, et al. Effect of omeprazole — a gastric proton pump inhibitor — on pentagastrin stimulated acid secretion in man. Gut 1983; 24: 270–6
Junghard O, Hassan-Alin M, Hasseigren G. The effect of the area under the plasma concentration vs time curve and the maximum plasma concentration of esomeprazole on intragastric pH. Eur J Clin Pharmacol 2002; 58: 453–8
Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors: focus on omeprazole, lansoprazole and pantoprazole. Clin Pharmacokinet 1996; 31: 9–28
Andersson T, Miners JO, Veronese ME, et al. Identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 1993; 36: 521–30
Li XQ, Weidolf L, Simonsson R, et al. Enantiomer/enantiomer interactions between the S- and R-enantiomers of omeprazole in human cytochrome P450 enzymes: major role of CYP2C19 and CYP3A4. J Pharmacol Experiment Ther 2005; 315: 777–87
Tybring G, Böttiger Y, Widen, et al. Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects. Clin Pharmacol Ther 1997; 62: 129–37
Hardman JG, Limbird LE, Gilman AG, editors. Goodman & Gilman’s the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001
Pichard L, Curi-Pedrosa R, Bonfils C, et al. Oxidative metabolism of lansoprazole by human liver cytochromes P450. Mol Pharmacol 1995; 47: 410–8
Shon DR, Kwon JT, Kim HK, et al. Metabolic disposition of lansoprazole in relation to the S-mephenytoin 4′-hydroxylation phenotype status. Clin Pharmacol Ther 1997; 61: 574–82
Schultz HU, Hartman M, Steinijans VW, et al. Lack of influence of pantoprazole on the disposition kinetics of theophylline in man. Int J Clin Pharmacol Ther Toxicol 1991; 29: 369–75
Yasuda S, Ohnishi A, Ogawa T, et al. Pharmacokinetic properties of E3810, a new proton pump inhibitor, in healthy male volunteers. Int J Clin Pharmacol Ther 1994; 32: 466–73
Yasuda S, Horai Y, Tomono Y, et al. Comparison of the kinetic disposition and metabolism of E3810, a new proton pump inhibitor, and omeprazole in relation to S-mephenytoin 4′-hydroxylation status. Clin Pharmacol Ther 1995; 58: 143–54
Ishizaki T, Horai Y. Cytochrome P450 and the metabolism of proton pump inhibitors: emphasis on rabeprazole. Aliment Pharmacol Ther 1999; 3: 27–36
Van den Branden M, Ring BJ, Binkley SN, et al. Interaction of human liver cytochrome P450 in vitro with LY307640, a gastric proton pump inhibitor. Pharmacogenetics 1996; 6: 81–91
Ieri I, Kishimoto Y, Okochi H, et al. Comparison of the kinetic disposition of and serum gastrin change by lansoprazole versus rabeprazole during an 8-day dosing scheme in relation to CYP2C19 polymorphism. Eur J Clin Pharmacol 2001; 57: 485–92
Pai V, Pai N. Randomized, double-blind, comparative study of dexrabeprazole 10mg versus rabeprazole 20mg in the treatment of gastroesophageal reflux disease. World J Gastroenterol 2007; 13(30): 4100–2
Andersson T, Röhss K, Bredberg E, et al. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 2001; 15: 1563–9
Lind T, Rydberg L, Kylebäck A, et al. Esomeprazole provides improved acid control versus omeprazole in patients with symptoms of gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000; 14: 861–7
Andersson T, Bredberg E, Sunzel M, et al. Pharmacokinetics (PK) and effect on pentagastrin stimulated peak acid output (PAO) of omeprazole (O) and its 2 optical isomers, S-omeprazole/esomeprazole (E) and R-omeprazole (R-O) [abstract]. Gastroenterology 2000; 118(A-5): 500
Röhss K, Lundin C, Rydholm H, et al. Esomeprazole 40 mg provides more effective acid control than omeprazole 40 mg. Am J Gastroenterol 2000; 95: 2432–3
Kahrilas PJ, Falk GW, Johnson DA, et al. Esomeprazole improves healing and symptom resolution as compared with omeprazole in reflux oesophagitis patients: a randomized controlled trial. Aliment Pharmacol Ther 2000; 14: 1249–58
Richter JE, Kahrilas PJ, Johanson J, et al. Efficacy and safety of esomeprazole compared with omeprazole in GERD patients with erosive esophagitis: a randomized controlled trial. Am J Gastroenterol 2001; 96: 656–65
Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) compared with lansoprazole (30 mg) in the treatment of erosive esophagitis. Am J Gastroenterol 2002; 97: 575–83
Labenz J, Armstrong D, Lauritsen K, et al. A randomized comparative study of esomeprazole 40mg versus pantoprazole 40mg for healing erosive oesophagitis: the EXPO study. Aliment Pharmacol Ther 2005; 21(6): 739–46
Labenz J, Armstrong D, Lauritsen K, et al. Esomeprazole 20mg vs. pantoprazole 20mg for maintenance therapy of healed erosive oesophagitis: results from the EXPO study. Aliment Pharmacol Ther 2005; 22(9): 803–11
Huber R, Kohl B, Sachs G, et al. The continuing development of proton pump inhibitors with particular reference to pantopra- zole. Aliment Pharmacol Ther 1995; 9: 363–78
Shirai N, Furuta T, Moriyama Y, et al. Effects of CYP2C19 genotypic differences in the metabolism of omeprazole and rabeprazole on intragastric pH. Aliment Pharmacol Ther 2001; 15: 1929–37
Regårdh CG, Gabrielsson M, Hoffmann KJ, et al. Pharmacokinetics and metabolism of omeprazole in animals and man: an overview. Scand J Gastroenterol Suppl. 1985; 108: 79–94
Miura M, Satoh S, Tada H, et al. Stereoselective metabolism of rabeprazole-thioether to rabeprazole by human liver microsomes. Eur J Clin Pharmacol 2006; 62: 113–7
Acknowledgements
This review was funded by AstraZeneca Mölndal.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Andersson, T., Weidolf, L. Stereoselective Disposition of Proton Pump Inhibitors. Clin. Drug Investig. 28, 263–279 (2008). https://doi.org/10.2165/00044011-200828050-00001
Published:
Issue Date:
DOI: https://doi.org/10.2165/00044011-200828050-00001