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 (K i = 32 μM) and CYP2D6 (K i = 367 μM) and a noncompetitive inhibitor of CYP2C9 (K i = 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.
Similar content being viewed by others
REFERENCES
Amsterdam, J. D., and Berwish, N. J. (1989). High dose tranylcypromine treatment for refractory depression. Pharmacopsychiatry 22:21-25.
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.
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.
Belanger, P. M., and Atitse-Gbeasson, A. (1982). Inhibitory effect of tranylcypromine on hepatic drug metabolism in the rat. Biochem. Pharmacol. 31:2679-2683.
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.
Callingham, B. A. (1993). Drug interactions with reversible monoamine oxidase-A inhibitors. Clin. Neuropharmacol. 16:S42-S50.
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.
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.
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.
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.
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.
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.
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.
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.
Fischer, W. (1991). The effects of (+)-and (-)-tranylcypromine as an anticonvulsive agent. Pharmazie 46:357-358.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Keltner, N. L., and Folks, D. C. (1997). Psychotropic Drugs, Mosby-Year Book, St. Louis, MO, pp. 103-111.
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.
Kline, N. S. (1958). Clinical experience with iproniazid (Marsilid). J. Clin. Exp. Psychopathol. 19:72-78.
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.
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.
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.
McDaniel, K. D. (1986). Clinical pharmacology of monoamine oxidase inhibitors. Clin. Neuropharmacol. 9:207-234.
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.
Palmer, T. (1995). Enzyme inhibition. In Palmer, T. (ed.), Understanding Enzymes, 4th edn., Prentice-Hall, Hertfordshire, UK, pp. 128-154.
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.
Pearlman, C. (1987). High dose tranylcypromine in refractory depression. J. Clin. Psychiatry 48:424-425.
Preskorn, S. H. (1996). Reducing the risk of drug-drug interaction: A goal of rational drug development. J. Clin. Psychiatry 57:3-6.
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.
Robinson, D. S. (1983). High dose monoamine oxidase-inhibitor therapy. J. Am. Med. Assoc. 250-2212.
Sandler, M. (1990). Monoamine oxidase inhibitors in depression: History and mythology. J. Psychopharmacol. 4:136-139.
Segel, I. H. (1993). Enzyme Kinetics: Behaviour and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems. Wiley, New York.
Smith, D. A. (1991). Species differences in metabolism and pharmacokinetics: Are we close to an understanding? Drug Metab. Rev. 23:355-373.
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.
Sovner, R. (1990). Amphetamine and tranylcypromine in treatment-resistant depression 'letter'. Biol. Psychiatry 28:1011-1012.
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.
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.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Salsali, M., Holt, A. & Baker, G.B. Inhibitory Effects of the Monoamine Oxidase Inhibitor Tranylcypromine on the Cytochrome P450 Enzymes CYP2C19, CYP2C9, and CYP2D6. Cell Mol Neurobiol 24, 63–76 (2004). https://doi.org/10.1023/B:CEMN.0000012725.31108.4a
Issue Date:
DOI: https://doi.org/10.1023/B:CEMN.0000012725.31108.4a