Drug Res (Stuttg) 2013; 63(09): 462-467
DOI: 10.1055/s-0033-1345163
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

The Inhibition of Monoamine Oxidase by Esomeprazole

A. Petzer
1   Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Potchefstroom, South Africa
A. Pienaar
2   Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa
J. P. Petzer
2   Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa
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received 11. März 2013

accepted 22. April 2013

15. Mai 2013 (online)


Virtual screening of a library of drugs has suggested that esomeprazole, the S-enantiomer of omeprazole, may possess binding affinities for the active sites of the monoamine oxidase (MAO) A and B enzymes. Based on this finding, the current study examines the MAO inhibitory properties of esomeprazole. Using recombinant human MAO-A and MAO-B, IC50 values for the inhibition of these enzymes by esomeprazole were experimentally determined. To examine the reversibility of MAO inhibition by esomeprazole, the recoveries of the enzymatic activities after dilution of the enzyme-inhibitor complexes were evaluated. In addition, reversibility of inhibition was also examined by measuring the recoveries of enzyme activities after dialysis of enzyme-inhibitor mixtures. Lineweaver-Burk plots were constructed to evaluate the mode of MAO inhibition and to measure Ki values. The results document that esomeprazole inhibits both MAO-A and MAO-B with IC50 values of 23 µM and 48 µM, respectively. The interactions of esomeprazole with MAO-A and MAO-B are reversible and most likely competitive with Ki values for the inhibition of the respective enzymes of 8.99 µM and 31.7 µM. Considering the available pharmacokinetic data and typical therapeutic doses of esomeprazole, these inhibitory potencies are unlikely to be of pharmacological relevance in humans. The MAO inhibitory effects of esomeprazole should however be taken into consideration when using this drug in animal experiments where higher doses are often administered.

  • References

  • 1 Abelö A, Andersson TB, Antonsson M et al. Stereoselective metabolism of omeprazole by human cytochrome P450 enzymes. Drug Metab Dispos 2000; 28: 966-972
  • 2 Tybring G, Böttiger Y, Widén J et al. Enantioselective hydroxylation of omeprazole catalyzed by CYP2C19 in Swedish white subjects. Clin Pharmacol Ther 1997; 62: 129-137
  • 3 Andersson T, Röhss K, Bredberg E et al. Pharmacokinetics and pharmacodynamics of esomeprazole, the S-isomer of omeprazole. Aliment Pharmacol Ther 2001; 15: 1563-1569
  • 4 Youdim MB, Bakhle YS. Monoamine oxidase: isoforms and inhibitors in Parkinson’s disease and depressive illness. Br J Pharmacol 2006; 147 (Suppl. 01) S287-S296
  • 5 Youdim MB, Edmondson D, Tipton KF. The therapeutic potential of monoamine oxidase inhibitors. Nat Rev Neurosci 2006; 7: 295-309
  • 6 Yamada M, Yasuhara H. Clinical pharmacology of MAO inhibitors: safety and future. Neurotoxicology 2004; 25: 215-221
  • 7 Fernandez HH, Chen JJ. Monoamine oxidase-B inhibition in the treatment of Parkinson’s disease. Pharmacotherapy 2007; 27: 174S-185S
  • 8 Finberg JP, Wang J, Bankiewicz K et al. Increased striatal dopamine production from L-DOPA following selective inhibition of monoamine oxidase B by R(+)-N-propargyl-1-aminoindan (rasagiline) in the monkey. J Neural Transm Suppl 1998; 52: 279-285
  • 9 Da Prada M, Zürcher G, Wüthrich I et al. On tyramine, food, beverages and the reversible MAO inhibitor moclobemide. J Neural Transm Suppl 1988; 26: 31-56
  • 10 Ramsay RR, Dunford C, Gillman PK. Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction. Br J Pharmacol 2007; 152: 946-951
  • 11 Stanford SC, Stanford BJ, Gillman PK. Risk of severe serotonin toxicity following co-administration of methylene blue and serotonin reuptake inhibitors: an update on a case report of post-operative delirium. J Psychopharmacol 2010; 24: 1433-1438
  • 12 Soriato G, Focati MP, Brescello R et al. Pharmaceutical preparations of crystalline lazabemide. Patent 2008; WO 2008010794
  • 13 Petzer A, Harvey BH, Wegener G, et al. Azure B. a metabolite of methylene blue, is a high-potency, reversible inhibitor of monoamine oxidase. Toxicol Appl Pharmacol 2012; 258: 403-409
  • 14 Novaroli L, Reist M, Favre E et al. Human recombinant monoamine oxidase B as reliable and efficient enzyme source for inhibitor screening. Bioorg Med Chem 2005; 13: 6212-6217
  • 15 Strydom B, Bergh JJ, Petzer JP. The inhibition of monoamine oxidase by 8-(2-phenoxyethoxy)caffeine analogues. Arzneimittelforschung 2012; 62: 513-518
  • 16 Harfenist M, Heuser DJ, Joyner CT et al. Selective inhibitors of monoamine oxidase. 3. Structure-activity relationship of tricyclics bearing imidazoline, oxadiazole, or tetrazole groups. J Med Chem 1996; 39: 1857-1863
  • 17 Manley-King CI, Bergh JJ, Petzer JP. Inhibition of monoamine oxidase by selected C5- and C6-substituted isatin analogues. Bioorg Med Chem 2011; 19: 261-274
  • 18 Dixon M. The determination of enzyme inhibitor constants. Biochem J 1953; 55: 170-171
  • 19 Aubin N, Barneoud P, Carter C et al. SL25.1131 [3(S),3a(S)-3-methoxymethyl-7-[4,4,4-trifluorobutoxy]-3,3a,4,5-tetrahydro-1,3-oxazolo[3,4-a]quinolin-1-one], a new, reversible, and mixed inhibitor of monoamine oxidase-A and monoamine oxidase-B: biochemical and behavioral profile. J Pharmacol Exp Ther 2004; 310: 1171-1182
  • 20 Chen JF, Steyn S, Staal R et al. 8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through dual actions of monoamine oxidase inhibition and A2A receptor antagonism. J Biol Chem 2002; 277: 36040-36044
  • 21 Binda C, Aldeco M, Geldenhuys WJ et al. Molecular insights into human monoamine oxidase B inhibition by the glitazone anti-diabetes drugs. ACS Med Chem Lett 2011; 3: 39-42
  • 22 Hughes JD, Blagg J, Price DA et al. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorg Med Chem Lett 2008; 18: 4872-4875
  • 23 Kalaria RN, Harik SI. Blood-brain barrier monoamine oxidase: enzyme characterization in cerebral microvessels and other tissues from six mammalian species, including human. J Neurochem 1987; 49: 856-864
  • 24 Boulton AA. Phenylethylaminergic modulation of catecholaminergic neurotransmission. Prog Neuropsychopharmacol Biol Psychiatry 1991; 15: 139-156
  • 25 Lasbennes F, Sercombe R, Seylaz J. Monoamine oxidase activity in brain microvessels determined using natural and artificial substrates: relevance to the blood-brain barrier. J Cereb Blood Flow Metab 1983; 3: 521-528
  • 26 Finberg JP, Lamensdorf I, Armoni T. Modification of dopamine release by selective inhibitors of MAO-B. Neurobiology (Bp) 2000; 8: 137-142
  • 27 Provost JC, Funck-Brentano C, Rovei V et al. Pharmacokinetic and pharmacodynamic interaction between toloxatone, a new reversible monoamine oxidase-A inhibitor, and oral tyramine in healthy subjects. Clin Pharmacol Ther 1992; 52: 384-393