Metabolism of Tranylcypromine-C<sup>14</sup> and dl-Amphetamine-C<sup>14</sup> in the Rat

Alleva, John J.

doi:10.1021/jm00342a001

Cited by 43 publications

(21 citation statements)

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“…The metabolite originating from hydrolysis is the para-methyl derivative of norephedrine, a psychoactive drug that is used as a stimulant, decongestant, and anorectic agent (Flavahan, 2005), suggesting that the M3 metabolite might have similar activities. Furthermore, both oxidations and aromatic hydroxylation are metabolic pathways typical of amphetamine-like compounds (Alleva, 1963;Dring et al, 1966;Ellison et al, 1966;Theobald and Maurer, 2007;Rohanova and Balikova, 2009;Maurer, 2010;Welter et al, 2014). However, the main metabolite found in both the plasma (A-C) Analysis was done in the same rats after the first dose (A), after the 14th dose (B), and after a 15th dose given after 48-hour washout (C).…”

Section: Discussionmentioning

confidence: 99%

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Lucchetti

Marzo

Passoni

et al. 2017

J Pharmacol Exp Ther

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para-Methyl-4-methylaminorex (4,49-DMAR) is a phenethylamine derivative with psychostimulant activity whose abuse has been associated with several deaths and a wide range of adverse effects. We recently validated a high-performance liquid chromatography-tandem mass spectrometry method to measure the compound's concentrations in plasma, and we applied it to describe the pharmacokinetic properties of 4,49-DMAR after a single dose in rats. In this study, we investigated the brain disposition and metabolism of cis-4,49-DMAR after intraperitoneal injection as well as its central behavioral effects. Locomotor activity increased after a single injection of 10 mg/kg, peaking at 2 hours and disappearing at 5 hours; in these conditions, brain absorption was very rapid, (t max 5 30-60 minutes) and large (brain-to-plasma ratio 5 24); the half-life was approximately 50 minutes. After 14 daily doses, the compound's effect on locomotor activity was greater (approximately 20% compared with the effect after the first dose), but not for pharmacokinetic reasons. Using high-resolution mass spectrometry, we also identified four metabolites of cis-4,49-DMAR in the plasma and brain of treated rats. Semiquantitative analysis indicated low brain permeability and very low brain concentrations, suggesting that these metabolites do not contribute to central behavioral effects; however, the metabolite originating from oxidation of the paramethyl group (M2) persisted in the plasma longer and at higher concentrations than the parent molecule and could be used to evaluate drug intake in human consumers. Finally, we describe the rewarding effect of cis-4,49-DMAR in the conditioning place preference test, suggesting a high risk of addiction in humans.

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Section: Discussionmentioning

confidence: 99%

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Lucchetti

Marzo

Passoni

et al. 2017

J Pharmacol Exp Ther

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“…11 However, there are conflicting reports as to whether tranylcypromine is metabolised to amphetamine and methamphetamine. 3,4,8,12,13 In the current case, tranylcypromine was detected in combination with amphetamine and methamphetamine in the urine sample of a fatal overdose case. One possible explanation for the presence of amphetamines in such postmortem specimens is the biotransformation of tranylcypromine to amphetamine and methamphetamine within the human body.…”

Section: Discussionmentioning

confidence: 58%

“…10 In another study, 5 mg/kg of tranylcypromine-14C was injected into animals in which approximately 4% of the injected drug was excreted unchanged and 12% was excreted as hippuric acid; in contrast, when amphetamine was injected, these values changed to 15% and 2%, respectively. 12 As such, the authors concluded that the opening of the cyclopropyl ring in tranylcypromine did not involve the formation of amphetamine. 12 Ragab et al noted that tranylcypromine is relatively stable on exposure to ultraviolet light and that only small amounts of degradation products can be detected using reversed-phase HPLC; the authors concluded that the cyclopropyl ring opens in both acidic and alkaline conditions and that the degradation products have different chemical structures from amphetamine and methamphetamine.…”

Section: Resultsmentioning

confidence: 98%

“…12 As such, the authors concluded that the opening of the cyclopropyl ring in tranylcypromine did not involve the formation of amphetamine. 12 Ragab et al noted that tranylcypromine is relatively stable on exposure to ultraviolet light and that only small amounts of degradation products can be detected using reversed-phase HPLC; the authors concluded that the cyclopropyl ring opens in both acidic and alkaline conditions and that the degradation products have different chemical structures from amphetamine and methamphetamine. 17 One possible explanation for the discrepancies in the findings of the aforementioned studies may be individual variations in drug metabolism among patients.…”

Section: Resultsmentioning

confidence: 98%

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Discrimination Between Drug Abuse and Medical Therapy: Case report of a tranylcypromine overdose-related fatality

Akhgari

Jokar

Etemadi-Aleagha

et al. 2017

SQUMJ

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abstract:Tranylcypromine is an effective antidepressant from the class of monoamine oxidase inhibitors and is structurally related to amphetamine. However, reports differ regarding the potential metabolism of tranylcypromine to amphetamine and methamphetamine within the human body. We report a 25-year-old woman with severe depression who died due to a fatal tranylcypromine overdose in 2016. She had been prescribed tranylcypromine one day previously and had no history of previous suicide attempts or substance abuse. The body was transferred to a forensic medicine department in Tehran, Iran for the autopsy. A urine sample was positive for tranylcypromine, amphetamine and methamphetamine using gas chromatography/mass spectrometry after derivatisation with heptafluorobutyric acid. As amphetamines were present in the urine sample, it was assumed that the tranylcypromine had been converted to amphetamines metabolically. As such, it is possible that the legitimate use of certain prescription drugs may complicate the interpretation of test results for illegal drugs.

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“…These findings prompted an investigation to establish whether desipramine was able to affect the formation of p-hydroxyamphetamine, the major metabolite of amphetamine in rats (Axelrod, 1954a, b;Alleva, 1963;Dring, Smith & Williams, 1966).…”

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confidence: 99%

Desipramine and amphetamine metabolism

Consolo

Dolfini

Garattini

et al. 1967

Journal of Pharmacy and Pharmacology

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Desipramine (2.5-5 mg/kg) increases the urinary excretion of amphetamine given intraperitoneally at doses of 75-15 mg/kg and it decreases the excretion ofp-hydroxyamphetamine. The rate of removal of brain amphetamine is decreased by desipramine (5 mg/kg, i.p.) when amphetamine is injected intraperitoneally but not when it is injected intracerebrally. It is suggested that desipramine impairs the hydroxylation of amphetamine in the liver thereby increasing the level of circulating amphetamine and eventually of brain amphetamine.MIPRAMINE and other tricyclic antidepressant agents are known to I increase and prolong the pharmacological effects of (+)-amphetamine showed that imipramine and desipramine prolong the hyperthermia induced by amphetamine in rats and that they also increase the amphetamine levels in brain and liver.These findings prompted an investigation to establish whether desipramine was able to affect the formation of p-hydroxyamphetamine, the major metabolite of amphetamine in rats (Axelrod, 1954a, b; Alleva, 1963; Dring, Smith & Williams, 1966). Materials and methodsMale Sprague-Dawley rats, 165 5 g, were kept in Makrolon cages at constant room temperature (22") and relative humidity (60%). (+)-Amphetamine sulphate and desipramine were injected intraperitoneally and the urines were collected 24 hr after dosing.Amphetamine and p-hydroxyamphetamine were determined in urine and amphetamine in brain by the method of Axelrod (1954 a, b). Free p-hydroxyamphetamine was determined in urines before acid hydrolysis. Suitable controls indicated that desipramine did not interfere with the determination of urinary amphetamine or p-hydroxyamphetamine. The brains of animals pretreated with desipramine (5 mg/kg i.p.) did not affect the recovery of (+)-amphetamine added in vitro.In some experiments (+)-amphetamine was introduced into the brain by the method of Valzelli (1964). Table 1 gives the results obtained on measuring amphetamine and p-hydroxyamphetamine in urines of rats treated with different doses of amphetamine alone or with desipramine. It is evident that desipramine treatment changed the pattern of amphetamine metabolism by increasing the urinary excretion of amphetamine and decreasing that of p-hydroxyamphetamine. Results

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Metabolism of Tranylcypromine-C¹⁴ and dl-Amphetamine-C¹⁴ in the Rat

Cited by 43 publications

References 0 publications

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Discrimination Between Drug Abuse and Medical Therapy: Case report of a tranylcypromine overdose-related fatality

Desipramine and amphetamine metabolism

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Metabolism of Tranylcypromine-C14 and dl-Amphetamine-C14 in the Rat

Cited by 43 publications

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Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Brain Disposition of cis-para-Methyl-4-Methylaminorex (cis-4,4′-DMAR) and Its Potential Metabolites after Acute and Chronic Treatment in Rats: Correlation with Central Behavioral Effects

Discrimination Between Drug Abuse and Medical Therapy: Case report of a tranylcypromine overdose-related fatality

Desipramine and amphetamine metabolism

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Product

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Metabolism of Tranylcypromine-C¹⁴ and dl-Amphetamine-C¹⁴ in the Rat