Advertisement

Cellular and Molecular Neurobiology

, Volume 24, Issue 1, pp 63–76 | Cite as

Inhibitory Effects of the Monoamine Oxidase Inhibitor Tranylcypromine on the Cytochrome P450 Enzymes CYP2C19, CYP2C9, and CYP2D6

  • Mahnaz Salsali
  • Andrew Holt
  • Glen B. Baker
Article

Abstract

1. The inhibitory effects of tranylcypromine, a nonselective irreversible inhibitor of monoamine oxidase (MAO), on three cytochrome P450 (CYP) enzymes, namely CYP2C9, CYP2C19, and CYP2D6, have been evaluated in vitro.

2. The studies were conducted using cDNA-expressed human CYP enzymes and probe substrates.

3. A range of substrate concentrations was coincubated with a range of tranylcypro- mine concentrations in the presence of each of the CYP enzymes at 37°C for a predetermined period of time. Product concentrations were quantified by HPLC with UV detection.

4. The results demonstrated that tranylcypromine is a competitive inhibitor of CYP2C19 (Ki = 32 μM) and CYP2D6 (Ki = 367 μM) and a noncompetitive inhibitor of CYP2C9 (Ki = 56 μM).

5. None of these inhibitory effects are considered clinically significant at usual therapeutic doses. However, in certain situations such as high dose tranylcypromine therapy, or in poor metabolizers of CYP2C19 substrates, clinically significant interactions might occur, particularly when tranylcypromine is coadministered with drugs with a narrow therapeutic index.

CYP enzymes tranylcypromine monoamine oxidase inhibitors dextromethorphan tolbutamide mephenytoin 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

REFERENCES

  1. Amsterdam, J. D., and Berwish, N. J. (1989). High dose tranylcypromine treatment for refractory depression. Pharmacopsychiatry 22:21-25.Google Scholar
  2. Baker, G. B., Coutts, R. T., McKenna, K. F., and Sherry-McKenna, R. L. (1992). Insights into the mechanisms of action of the MAO inhibitors phenelzine and tranylcypromine: A review. J. Psychiatry Neurosci. 17:206-214.Google Scholar
  3. Baker, G. B., Urichuk, L. J., and Coutts, R. T. (1998). Drug metabolism and metabolic drug-drug interactions in psychiatry. Child Adolesc. Psychopharmacol. News Suppl. 1-8.Google Scholar
  4. Belanger, P. M., and Atitse-Gbeasson, A. (1982). Inhibitory effect of tranylcypromine on hepatic drug metabolism in the rat. Biochem. Pharmacol. 31:2679-2683.Google Scholar
  5. Boobis, A. R., Sesardic, D., Murray, B. P., Edwards, R. J., Singleton, A. M., Rich, K. J., Murray, S., De La Torre, R., Segura, J., Pelkonen, O., Pasanen, M., Kobayashi, S., Zhi-Guang, T., and Davies, D. S. (1990). Species variation in the response of the cytochrome P-450-dependent monooxygenase system to inducers and inhibitors. Xenobiotica 20:1139-1161.Google Scholar
  6. Callingham, B. A. (1993). Drug interactions with reversible monoamine oxidase-A inhibitors. Clin. Neuropharmacol. 16:S42-S50.Google Scholar
  7. Calverley, D. G., Baker, G. B., Coutts, R. T., and Dewhurst, W. G. (1981). A method for measurement of tranylcypromine in rat brain regions using gas chromatography with electrochemical detection. Biochem. Pharmacol. 30:861-867.Google Scholar
  8. Chiba, K., and Kobayashi, K. (2000). Antidepressants. In Levy, R. H., Thummel, K. E., Trager, W. F., and Eichelbaum, M. (eds.), Metabolic Drug Interactions, Lippincott, Williams & Wilkins, Philadelphia, pp. 233-243.Google Scholar
  9. Chiba, K., Manabe, K., Kobayashi, K., Takayama, Y., Tani, M., and Ishizaki, T. (1993). Development and preliminary application of a simple assay of S-mephenytoin 4-hydroxylase activity in human liver microsomes. Eur. J. Clin. Pharmacol. 44(6):559-562.Google Scholar
  10. Clark, B., Thompson, J. W., and Widdington, G. (1972). Analysis of the inhibition of pethidine N-demethylation by monoamine oxidase inhibitors and some other drugs with special reference to drug interactions in man. Br. J. Pharmacol. 44 89-99.Google Scholar
  11. Coutts, R. T., Rao, T. S., Baker, G. B., Micetich, R. G., and Hall, T. W. E. (1987). Neurochemical and neuropharmacological properties of 4-fluorotranylcypromine. Cell. Mol. Neurobiol. 7:271-290.Google Scholar
  12. Crane, G. E. (1957). Iproniazid (Marsilid) phosphate, a therapeutic agent for mental disorders and debilitating disease. Psychiatr. Res. Rep. Am. Psychiatr. Assoc. 8:142-152.Google Scholar
  13. Dupont, H., Davies, D. S., and Strolin-Benedetti, M. (1987). Inhibition of cytochrome P450-dependent oxidation reactions by MAO inhibitors in rat liver microsomes. Biochem. Pharmacol. 36:1651-1657.Google Scholar
  14. Eade, N. R., and Renton, K. W. (1970). Effects of monoamine oxidase inhibitors on the N-demethylation and hydrolysis of meperidine. Biochem. Pharmacol. 19:2243-2250.Google Scholar
  15. Fischer, W. (1991). The effects of (+)-and (-)-tranylcypromine as an anticonvulsive agent. Pharmazie 46:357-358.Google Scholar
  16. Fuentes, J. A., Oleshansky, M. A., and Neff, N. H. (1976). Comparison of apparent antidepressant activity of (+)-and (-)-tranylcypromine in an animal model. Biochem. Pharmacol 25:801-804.Google Scholar
  17. Greenblatt, D. J., Von Moltke, L. L., Harmatz, J. S., and Shader, R. I. (2002). Pharmacokinetics, pharmacodynamics, and drug disposition. In Davis, K. L., Charney, D., Coyle, J. T., and Nemeroff, C. (eds.), Neuropsychopharmacology: The Fifth Generation of Progress, Lippincott, Williams & Wilkins, Philadelphia, pp. 507-524.Google Scholar
  18. Guze, B. H., and Baxter, L. R., jrJr. (1987). Refractory depression treated with high doses of a monoamine oxidase inhibitor. J. Clin. Psychiatry 48:31-32.Google Scholar
  19. Hartter, S., Tybring, G., Friedberg, T., Weigmann, H., and Hiemke, C. (2002). The N-demethylation of the doxepin isomers is mainly catalyzed by the polymorphic CYP2C19. Pharm. Res. 19:1034-1037.Google Scholar
  20. Himmelhoch, J. M. (1995). Monoamine oxidase inhibitors. In Kaplan, H. I., Sadock, B. J. (ed.), Kaplan and Sadock's Comprehensive Textbook of Psychiatry, Lippincott, Williams and Wilkins, Baltimore, pp. 2038-2055.Google Scholar
  21. Himmelhoch, J. M., Fuchs, C. Z., and Symons, B. J. (1982). A double-blind study of tranylcypromine treatment of anergic bipolar depression. J. Nerv. Ment. Dis. 170:628-634.Google Scholar
  22. Himmelhoch, J. M., Thase, M. E., Mallinger, A. G., and Houck, P. (1991). Tranylcypromine vs imipramine in anergic bipolar depression. Am. J. Psychiatry 148:910-916.Google Scholar
  23. Inaba, T., Jurima, M., Mahon, W. A., and Kalow, W. (1985). In vitro inhibition studies of two isozymes of human liver cytochrome P450: Mephenytoin p-hydroxylase and sparteine monooxygenase. Drug Metab. Dispos. 13:443-448.Google Scholar
  24. Keck, P. E., Carter, W. P., Nierenberg, A. A., Cooper, T. B., Potter, W. Z., and Rothschid, A. J. (1991). Acute cardiovascular effects of tranylcypromine: Correlation with plasma drug, metabolite, norepinephrine, and MHPG levels. J. Clin. Psychiatry 52:250-254.Google Scholar
  25. Keltner, N. L., and Folks, D. C. (1997). Psychotropic Drugs, Mosby-Year Book, St. Louis, MO, pp. 103-111.Google Scholar
  26. Ketter, T. A., Post, R. M., Parekh, P. I., and Worthington, K. (1995). Addition of monoamine oxidase inhibitors to carbamazepine: Preliminary evidence of safety and antidepressant efficacy in treatment-resistant depression. J. Clin. Psychiatry 56:471-475.Google Scholar
  27. Kline, N. S. (1958). Clinical experience with iproniazid (Marsilid). J. Clin. Exp. Psychopathol. 19:72-78.Google Scholar
  28. Korzekwa, K. R., Krishnamachary, N., Shou, M., Ogai, A., Parise, R. A., Rettie, A. E., Gonzalez, F. J., and Tracy, T. S. (1998). Evaluation of atypical cytochrome P450 kinetics with two-substrate models: Evidence that multiple substrates can simultaneously bind to cytochrome P450 active sites. Biochemistry 37:4137-4147.Google Scholar
  29. Mallinger, A. G., Edwards, D. J., Himmelhoch, J. M., Knopf, S., and Elher, J. (1986). Pharmacokinetics of tranylcypromine in patients who are depressed: Relationship to cardiovascular effects. Clin. Pharmacol. Ther. 40:444-450.Google Scholar
  30. Martin, L., Bakish, D., and Joffe, R. (1994). MAO inhibitor treatment of depression. In Kennedy, S. H. (ed.), Clinical Advances in Monoamine Oxidase Inhibitor Therapies, American Psychiatric Press, Washington, DC, pp. 147-180.Google Scholar
  31. McDaniel, K. D. (1986). Clinical pharmacology of monoamine oxidase inhibitors. Clin. Neuropharmacol. 9:207-234.Google Scholar
  32. Nies, A., and Robinson, D. S. (1982). Monoamine oxidase inhibitors. In Paykel, E. S. (ed.), Handbook of Affective Disorders, Guilford Press, New York, pp. 246-261.Google Scholar
  33. Palmer, T. (1995). Enzyme inhibition. In Palmer, T. (ed.), Understanding Enzymes, 4th edn., Prentice-Hall, Hertfordshire, UK, pp. 128-154.Google Scholar
  34. Parkinson, A. (1996). Biotransformation of xenobiotics. In Klaassen, C. D. (ed.), Casarett and Doull's Toxicology: The Basic Science of Poisons, McGraw-Hill, New York, pp. 113-186.Google Scholar
  35. Pearlman, C. (1987). High dose tranylcypromine in refractory depression. J. Clin. Psychiatry 48:424-425.Google Scholar
  36. Preskorn, S. H. (1996). Reducing the risk of drug-drug interaction: A goal of rational drug development. J. Clin. Psychiatry 57:3-6.Google Scholar
  37. Preskorn, S. H. (1997). Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin. Pharmacokinet. 32(Suppl. 1):1-21.Google Scholar
  38. Robinson, D. S. (1983). High dose monoamine oxidase-inhibitor therapy. J. Am. Med. Assoc. 250-2212.Google Scholar
  39. Sandler, M. (1990). Monoamine oxidase inhibitors in depression: History and mythology. J. Psychopharmacol. 4:136-139.Google Scholar
  40. Segel, I. H. (1993). Enzyme Kinetics: Behaviour and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems. Wiley, New York.Google Scholar
  41. Smith, D. A. (1991). Species differences in metabolism and pharmacokinetics: Are we close to an understanding? Drug Metab. Rev. 23:355-373.Google Scholar
  42. Smith, S. E., Lambourn, J., and Tyrer, P. J. (1980). Antipyrine elimination by patients under treatment with monoamine oxidase inhibitors. Br. J. Clin. Pharmacol. 9:21-25.Google Scholar
  43. Sovner, R. (1990). Amphetamine and tranylcypromine in treatment-resistant depression 'letter'. Biol. Psychiatry 28:1011-1012.Google Scholar
  44. Spahn-Langguth, H., Hahn, G., and Mutschler, E. (1992). Enantiospecific high-performance liquid chromatography assay with fluorescence detection for the monoamine oxidase inhibitor tranylcypromine and its applicability in pharmacokinetic studies. J. Chromatogr. 584:229-237.Google Scholar
  45. Thase, M. E., Kupfer, D. J., Frank, E., and Jarrett, D. B. (1989). Treatment of imipramine-resistant recurrent depression: II. An open clinical trial of lithium augmentation. J. Clin. Psychiatry 50:413-417.Google Scholar

Copyright information

© Plenum Publishing Corporation 2004

Authors and Affiliations

  • Mahnaz Salsali
    • 1
  • Andrew Holt
    • 1
  • Glen B. Baker
    • 1
  1. 1.Neurochemical Research Unit, Department of PsychiatryUniversity of AlbertaEdmontonCanada

Personalised recommendations