Deprenyl is metabolized to methamphetamine and amphetamine in man.

Reynolds, G.P.; Elsworth, J. D.; Blau, Karl; Sandler, M.; Lees, Andrew J.; Stern, Gerald

doi:10.1111/j.1365-2125.1978.tb00883.x

Cited by 277 publications

(78 citation statements)

References 16 publications

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“…This suggests that the inhibitor does not further accumulate in the brain after the first few days, presumably reflecting a rapid metabolism to amphetamine and methamphetamine (Reynolds, Elsworth, Blau, Sandler, Lees & Stern, 1978). These results are consistent with those of , who show no clinically significant change in tolerance to tyramine after 18 months treatment and they serve to underline the safety of the drug in clinical practice (Birkmayer et al, 1977;Lees et al, 1977 Received October 8,1979 …”

Section: Moon Hk and Holler Ch (1970supporting

confidence: 78%

Deprenyl is a selective inhibitor of brain MAO‐B in the long‐term treatment of Parkinsons's disease.

Reiderer¹,

Reynolds²

1980

Brit J Clinical Pharma

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Section: Moon Hk and Holler Ch (1970supporting

confidence: 78%

Deprenyl is a selective inhibitor of brain MAO‐B in the long‐term treatment of Parkinsons's disease.

Reiderer¹,

Reynolds²

1980

Brit J Clinical Pharma

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“…The primary metabolites of selegiline in humans are desmethylselegiline and methamphetamine (Reynolds et al, 1978;Shin, 1997). Amphetamine is a secondary product formed by dealkylation of either of the two compounds (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Originally, methamphetamine (MA) and amphetamine (A) were identified as the major metabolic products in human urine and depropargylation with subsequent demethylation was postulated as a key metabolic pathway of the drug (Reynolds et al, 1978). Subsequently, a second major pathway, via desmethylselegiline (DMS), was reported (Yoshida et al, 1986).…”

mentioning

confidence: 99%

Comparative Studies on the Cytochrome P450-Associated Metabolism and Interaction Potential of Selegiline Between Human Liver-Derived in Vitro Systems

Salonen

Nyman²,

Boobis³

et al. 2003

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Selegiline was used as a model compound in a project aimed at comparing, evaluating, and integrating different in vitro approaches for the prediction of cytochrome P450 (P450)-catalyzed hepatic drug metabolism in humans (EUROCYP). Metabolic predictions were generated using homology modeling, cDNA-expressed P450 enzymes, human liver microsomes, primary cultured human hepatocytes, and precision-cut human liver slices. All of the in vitro systems correctly indicated the formation of two dealkylated metabolites, desmethylselegiline and methamphetamine. The metabolic instability of selegiline was demonstrated by all of the in vitro systems studied. Estimates of clearance varied from 16 l/h to 223 l/h. With the exception of one approach, all systems underpredicted the in vivo clearance in humans (236 l/h). Despite this, all approaches successfully classified selegiline as a high clearance compound. Homology modeling suggested the participation of CYP2B6 in the demethylation of selegiline and of CYP2D6 in the depropargylation of the drug. Studies with recombinant expressed enzymes and with human hepatic microsomal fraction supported the involvement of CYP2B6 but not of CYP2D6. These techniques also suggested the involvement of CYP1A2, CYP2C8, and CYP2C19 in the biotransformation of selegiline. In vitro, CYP2B6 was the most active form of P450 involved in selegiline metabolism. Metabolism by several enzymes operating in parallel implies a low interaction potential for the drug. None of the techniques alone was able to predict all aspects of the metabolic and kinetic behavior of selegiline in vivo. However, when used as an integrated package, all significant characteristics were predictable.For more than a decade, in vitro techniques have had a well established role in the early phases of drug development in predicting the pharmacokinetic and metabolic behavior of new chemical entities. When properly used, predictions based on results from in vitro studies will save both development costs and time. In addition, they greatly reduce the number of experimental animals used by the industry in absorption, distribution, metabolism, and excretion studies. Support for the increased utilization of in vitro techniques in drug metabolism studies has come from regulatory authorities (CDER/FDA, 1997). Most of these techniques are easily applicable to high throughput screening, which has further promoted their use recently (Rodrigues, 1997).Several in vitro methods for metabolic predictions are in common use, and even commercially available, but little attention has been paid to the validation of the systems in terms of quality of the predictions obtained and their usefulness in the process of drug development. In particular, comparisons of the data produced by different systems have been scarce. The present study was part of the EUROCYP project within the Biomed2 (Framework IV) program of the European Union. The goals of the project were to evaluate, compare, a...

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“…The e ect of selegiline on dopamine release could be the result of an amphetamine-like action, either of the parent molecule or metabolites, because selegiline is metabolized to (7)-methamphetamine and (7)-amphetamine (Reynolds et al, 1978). However, rasagiline is not metabolized to amphetamine-like metabolites but to 1-aminoindane which does not possess amphetamine-like properties (Finberg et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Effect of low‐dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine‐induced dopamine release in vivo

Lamensdorf¹,

Porat

Simantov

et al. 1999

British J Pharmacology

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1 Chronic treatment with low doses of the selective monoamine oxidase (MAO) type B inhibitors selegiline [(7)-deprenyl] and rasagiline, causes elevation in extracellular level of 3,4-dihydroxyphenylethylamine (dopamine) in the rat striatum in vivo (Lamensdorf et al., 1996). The present study was carried out to determine whether this e ect of selegiline could be the result of an inhibition of the high-a nity dopamine neuronal transport process. 2 Changes in activity of the dopamine transporter (DAT) in vivo following selegiline treatment were evaluated indirectly by microdialysis technique in the rat, from the change in striatal dopamine extracellular concentration following systemic amphetamine administration (4 mg kg 71 , i.p.). Striatal levels of the DAT molecule were determined by immunoblotting. Uptake of [ 3 H]-dopamine was determined in synaptosomes from selegiline-treated animals. 3 Amphetamine-induced increase in striatal extracellular dopamine level was attenuated by one day and by chronic (21 days) treatment with selegiline (0.25 mg kg 71 , s.c.). 4 Striatal levels of DAT were elevated after 1 and 21 days treatment with selegiline, but were not a ected by clorgyline, rasagiline, nomifensine or amphetamine. 5 The increase in DAT expression, and attenuation of amphetamine-induced dopamine release, were not accompanied by a change in [ 3 H]-dopamine uptake in synaptosomes of selegiline-treated animals. 6 The results suggest that a reversible inhibition of dopamine uptake occurs following chronic low dose selegiline treatment in vivo which may be mediated by an increase in endogenous MAO-B substrates such as 2-phenylethylamine, rather than by the inhibitor molecule or its metabolites. Increased DAT expression appears to be a special property of the selegiline molecule, since it occurs after one low dose of selegiline, and is not seen with other inhibitors of MAO-A or MAO-B. The new DAT molecules formed following selegiline treatment appear not to be functionally active.

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Deprenyl is metabolized to methamphetamine and amphetamine in man.

Cited by 277 publications

References 16 publications

Deprenyl is a selective inhibitor of brain MAO‐B in the long‐term treatment of Parkinsons's disease.

Deprenyl is a selective inhibitor of brain MAO‐B in the long‐term treatment of Parkinsons's disease.

Comparative Studies on the Cytochrome P450-Associated Metabolism and Interaction Potential of Selegiline Between Human Liver-Derived in Vitro Systems

Effect of low‐dose treatment with selegiline on dopamine transporter (DAT) expression and amphetamine‐induced dopamine release in vivo

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