Summary
It is well established in the litrature, that selegiline is metabolised to itsN-dealkylated metabolites,N-desmethylselegiline, methamphetamine and amphetamine. However, most studies on selegiline metabolism did not characterize the species differences in the formation of the metabolites. Therefore, in this study, we investigated the in vitro metabolism of selegiline in liver microsomes of different species. In addition, to the previously well-characterized metabolites, selegiline-N-oxide (selegiline-NO) was found to be formed as a metabolite of selegiline in rat liver microsomal preparation. The results of experiments with liver microsomes from other species indicated species differences in the rate and extent of formation of selegiline-NO. The dog and hamster liver microsomal preparations were the most active in terms of selegiline-NO production, whereas little selegiline was metabolized to itsN-oxide in human liver microsomes. When selegiline-NO was incubated with rat liver microsomes, no metabolism occurred. When a short incubation time was applied in selegiline expriments no increase in the amount of selegiline-NO was detected. Accordingly, it was clear that selegiline was not metabolized to theN-dealkylated orN,N-bis-dealkylated compounds via selegiline-NO. Studies with different isoenzyme inhibitors indicated that the formation of selegiline-NO might be catalyzed at least partly by cytochrome P450 (CYP) 2D6 and CYP3A4. With the exception of hamster microsomes in the microsomal preparations in vitro, the formation of theR,S-stereoisomer of selegiline-NO was preferred.
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Heinonen, E.H., Anttila, M.I., Lammintausta, R.A.S., (1993): Pharmacokinetics and clinical pharmacology of deprenyl. In I. Szelényi (Ed.), Inhibitors of monoamine oxidase B — Pharmacology and clinical use in neurodegenerative disorders, Birkhäuser Verlag Basel/Switzerland,, pp. 201–213
Ecsery, Z., Müller, M., Knoll, J., Somfai, É.,(1962): Hung. Pat. 151,090 Chem. Abstr.60,11939d
Ecsery. Z., Kósa, I., Knoll, J., Somfai, É., (1965): Neth. Appl. 6,605,956 Chem. Abstr. 67,2161 ly
Gyarmati, L., Plachy, J., Sátory, É, Rácz, I., Tamás, J., (1975): A contribution to the metabolism of Deprenyl. Acta Pharmaceutica Hungarica, 45, 139–144.
Magyar, K., Skolnik, J., Knoll, J., (1968): Radiopharmacological analytic studies with deprenyl-14C. In Leszkowszky, G.P. (Ed.), V. Conferencia Hungarica pro Therapia et Investigatione in Pharmacologia, Budapest Hungarian Academy of Sciences, Budapest, pp. 103–109.
Reynolds, G.P., Riederer, P., Sandler, M., Jellinger, K., Seemann, D., (1978): Amphetamine and 2-phenylethylamine in post-mortem Parkinsonian brain after (−)-deprenyl administration. J. Neural Transmission. 43, 271–277.
Reynolds, G.P., Elsworth, J.D., Blau, K., Sandler, M., Lees, A.J., Stern, G.M., (1978): Deprenyl is metabolized to methamphetamine and amphetamine in man. Br. J. Clin. Pharm. 6, 542–544.
Sandler, M., Glover, V., Ashford, A., Stern, G.M., (1978): Absence of “Cheese effect” during deprenyl therapy: some recent studies, J. Neural Transmission. 43, 209–215.
Chrisp, P., Mammen, G.J., Sorkin, E.M., (1991): Deprenyl — A review of its pharmacology, symptomatic benefits and protective potencial in Parkinson’s disease. Drugs Aging, 1, 228–248.
Gerlach, M., Youdim, M.B.H., Riederer, P., (1996): Pharmacology of deprenyl. Neurology, 47 Suppl. 3, S137-S145.
Heinonen, E.H., Lammintausta, R., (1991): A review of the pharmacology of deprenyl. Acta Neurologica Scandinavica [Suppl.], 136, 44–59.
Heinonen, E.H., (1995): Deprenyl in the treatment of Parkinson’s disease — Pharmacokinetic and clinical studies. Academic Dissertation, University of Turku, Turku, Finland, Publ.: Serioffset, Turku.
Lavelle, Th., Heinonen, E.H., (1992): Pharmacokinetics of Eldepryl®. In Eldepryl® (Deprenyl hydrochloride) — A new therapeutic era in Parkinson’s disease-Product Monograph, Adis International Limited, Chester, pp. 16–17.
Magyar, K., (1993): Pharmacology of monoamine oxidase type B inhibitors. In Szelényi I. (Ed.), Inhibitors of monoamine oxidase B-Pharmacology and clinical use in neurodegenerative disorders Birkhäuser Verlag Basel/Switzerland, pp. 125–143
Mahmood, I., (1997): Clinical pharmacokinetics and pharmacodynamics of deprenyl — An update. Clin. Pharmacokin. 33, 91–102.
Szatmári, I., Tóth, K., (1992): Pharmacokinetics and metabolism of deprenyl. Acta Pharmaceutica Hungarica. 62, 243–247.
Szatmári, I., (2001): Pharmacokinetic and metabolic characteristics of Deprenyl. In Magyar K. and Vizi E.S. (Eds.), Milestones in monoamine oxidase research: discovery of (−)-deprenyl. Mediana Publishing House, Budapest, pp. 61–80.
Yoshida, T., Yamada, Y., Yamamoto, T., Kuroiwa, Y., (1986): Metabolism of deprenyl, a selective monoamine oxidase (MAO) B inhibitor in rat: relationship of metabolism to MAO-B inhibitory potency. Xenobiotica, 16, 129–136.
Grace, J.M., Kinter, M.T., Macdonald, T.L., (1994): Atypical Metabolism of deprenyl and its enantiomer, (S)-(+)-N,α-Dimethyl-N-propynylphenethylamine, by cytochrome P4502D6. Chem. Res. Toxicol. 7, 286–290.
Wacher, V.J., Wong, S., Wong, HT., Benet, L.Z., (1996): Contribution of CYP3A to deprenyl metabolism in rat and human microsomes. In ISSX Proceedings 10, 7th North American ISSX Meeting, San Diego, California US A, pp. 351
Taavitsainen, P., Anttila, M., Nyman, L., Karnani, H., Pelkonen, O., (1998): Cytochrome P450 enzymes and metabolism of deprenyl: the in vitro study in human liver microsomes. Exp. Toxicol. Pathology, 50, 138.
Taavitsainen, P., Anttila, M., Nyman, L., Karnani, H., Salonen J.S., Pelkonen, O., (2000): Selegiline metabolism and cytochrome P450 enzymes: in vitro study in human liver microsomes. Pharmacol. Toxicol. 86, 215–221.
Valoti, M., Fusi F., Frosini M, Pessina F, Tipton K.F., Sgaragli G.P., (2000): Cytochrom P450-dependent N-dealkylation of L-deprenyl in C57BL mouse liver microsomes: effects of in vivo and in vivo treatment with ethanol, phenobarbital, beta-naphtoflavone and L-deprenyl. Eur. J.Pharmacol. 391, 199–206.
Scheinin, H., Anttila, M., Dahl, M-L., Karnani, H., Nyman, L., Taavitsainen, P., Pelkonen, O., Bertilsson, L., (1998): CYP2D6 polymorphism is not crucial for the disposition of deprenyl. Clin. Pharm. Ther. 64, 402–411
Wu, R-F., Ichikawa, Y., (1995): Inhibition of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine metabolic activity of porcine FAD-containin monooxygenase by selective monoamine oxidase-B inhibitors. FEBS Letters, 358, 145–148.
Schachter, M., Mardsen, C.D., Parkes, J.D., Jenner, P., Testa, B., (1980): Deprenyl in the management of response fluctuations in patients with Parkinson’s disease on levodopa. J. Neurology, Neurosurgery and Psychiatry. 43, 1016–1021.
Meeker, J.E., Reynolds, Ph.C., (1990): Postmortem tissue methamphetamine concentrations following deprenyl administration. J. Anal. Toxicol. 14, 330–331.
Szökö, É., Magyar, K., (1996): Enantiomer identification of the major metabolites of (−)deprenyl in rat urine by capillary electrophoresis. Int. J. Pharm. Advances. 1, 320–328.
Shin, H-S., (1997): Metabolism of deprenyl in humans — Identification, excretion and stereochemistry of urine metabolites. Drug Metab. Dispos. 25, 657–662.
Lévai, F., Fejér E., Szabó A., Erőss-Takácsi T., Szebeni Gy., Szatmári I, Hermecz L, (2000): Study on the in vitro metabolism of selegiline on microsomes. Symposium on pharmacokinetics and metabolism. Mátraháza, Hungary, Proceedings, pp. 46.
Guengerich, F.P., (1989): In Hayes, A.V. (Ed.), Principles and Methods of Toxicology Raven Press, Ltd., NewYork, pp. 777.
Lowry, O.H., Rosenbrough, N.J., Farr, A.L., Randall, R.J., (1951): Protein determination with the folin phenol reagent. J. Biol. Chem. 193. 265–275.
Newton, D.J., Wang, R.W., Lu, A.Y.H., (1995): Cytochrome P450 inhibitors: Evaluation of specificities in the in vitro metabolism of therapeutic agents by human liver microsomes. Drug Metab. Dispos. 23, 154–158.
Magyar, K., Szüts, T., (1982): The fate of (−)-deprenyl in the body — Preclinical studies. In Szebeni, R. (Ed.), Proceedings of the international symposium on (−)-deprenyl, Jumex, Szombathely, Hungary Chinoin, Budapest, pp. 25–31.
Katagi, M., Tatsuno, M., Miki, A., Nishikawa, M., Nakajima, K., Tsuchihashi, H., (2001): Simultaneous determination of selegiline-N-oxide, a new indicator for selegiline administration, and other meabolites in urine by high-performance liquid chromatography-electrospray ionization mass spectrometry. J. Chromatogr. B. 759, 125–133.
Katagi, M., Tatsuno, M., Tsutsumi, H., Miki, A., Nishioka, K., Nakajima, K., Nishikawa, M., Tsuchihashi, H., (2002): Urinary excretion of selegiline N-oxide, a new indicator for selegiline administration in man. Xenobiotica. 32, 823–831.
Bach, M.V., Couts, T.T., Baker, G.B., (2000): Metabolism of N,N-dialkylated amphetamines, including deprenyl, by CYP2D6 expressed in a human cell line. Xenobiotica. 30, 297–306.
Weli A.M., Lindeke B., (1986) Peroxidative N-oxidation and N-dealkylation Tactions with pargyline. Xenobiotica. 16, 281–288.
Boulton, A.A., Davis, B.A., Durden, D.A., Dyck, L.E., Juorio, A.V., Li, X-M., Paterson, I.A., Yu, P.H., (1997): Aliphatic propargylamines: New antiapoptotic drugs. Drug Dev. Res. 42, 150–156.
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Lévai, F., Fejér, E., Szeleczky, G. et al. In vitro formation of selegiline-N-oxide as a metabolite of selegiline in human, hamster, mouse, rat, guinea-pig, rabbit and dog. European Journal of Drug Metabolism and Pharmacokinetics 29, 169–178 (2004). https://doi.org/10.1007/BF03190594
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DOI: https://doi.org/10.1007/BF03190594