MAO (monoamine oxidase)

Peroxynitrite is a reactive nitrogen species produced in the intravascular compartment from superoxide anion and nitric oxide. Peroxynitrite destroys blood plasma proteins and membranes of red blood cells and of platelets. This explains why excessive production of peroxynitrite contributes to diseases and to ageing. Therapeutics that antagonize peroxynitrite may delay ageing and the progression of disease. We developed an in vitro assay that allows the investigation of the oxidative damage caused by peroxynitrite in the intravascular compartment. This assay correlates the damage with the rate of formation of protein carbonyl groups, 3-nitrotyrosine (3-NT) and thiobarbituric acid reactive substances. Using this assay, we evaluated the ability of phenelzine, a scavenger of reactive aldehydes, to antagonize the effects of peroxynitrite. Herein, we showed that phenelzine significantly decreased the lipid peroxidative damage caused by peroxynitirite in blood plasma and platelets. Moreover, it inhibited carbonyl group and 3-NT formation in blood plasma and platelet proteins[1].

In mice, intraperitoneal injection of phenelzine immediately after severe thoracic compression, and thereafter once daily for 6 weeks, improved hind limb function, reduced astrogliosis and promoted axonal regrowth/sprouting at 4 and 5 weeks after spinal cord injury compared to vehicle control-treated mice. Phenelzine application upregulated L1 expression in the spinal cord and stimulated the cognate L1-mediated intracellular signaling cascades in the spinal cord tissue. Phenelzine-treated mice showed decreased levels of pro-inflammatory cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor-α in the injured spinal cord during the acute phase of inflammation[2].

This study developed an in vitro assay that allows the investigation of the oxidative damage caused by peroxynitrite in the intravascular compartment. This assay correlates the damage with the rate of formation of protein carbonyl groups, 3-nitrotyrosine (3-NT) and thiobarbituric acid reactive substances. Using this assay, this study evaluated the ability of phenelzine, a scavenger of reactive aldehydes, to antagonize the effects of peroxynitrite. Herein, this study showed that phenelzine significantly decreased the lipid peroxidative damage caused by peroxynitirite in blood plasma and platelets[1].

In mice, intraperitoneal injection of phenelzine immediately after severe thoracic compression, and thereafter once daily for 6 weeks, improved hind limb function, reduced astrogliosis and promoted axonal regrowth/sprouting at 4 and 5 weeks after spinal cord injury compared to vehicle control-treated mice[2].

Absorption, Distribution and Excretion
Phenelzine is rapidly absorbed from the gastrointestinal tract. The decay of the drug action is not dependent on the pharmacokinetic parameters but on the rate of protein synthesis which restores the functional levels of monoamine oxidase. The mean Cmax is 19.8 ng/ml and it occurs after 43 minutes of dose administration.
The elimination of the administered dose is mainly composed of the phenelzine metabolites, phenylacetic acid and parahydroxyphenylacetic acid that constitute 79% of the dose found in the urine in the first 96 hours.
The volume of distribution of phenelzine is hard to determine as drugs from this kind penetrate the CNS very well into the tissue where their activity is desired.
Following ip injection of 2.5 mg/kg bw phenelzine-1-(14)C sulfate to rats, 62% of the dose was recovered in the urine within 24 hours.
Following a single 30 mg dose of Nardil (2 X 15 mg tablets), a mean peak plasma concentration (Cmax) of 19.8 ng/mL occurred at a time (Tmax) of 43 minutes post dose.
Phenelzine is readily absorbed from the gastrointestinal tract. There is little excretion in the urine.

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Metabolism / Metabolites
For the metabolic studies, it is assumed that phenelzine is acetylated. Some of the metabolites of phenelzine are phenylacetic acid, 2-phenylethylamine and 4-hydroxyphenylacetic acid as major metabolites and N-acetyl-phenelzine as a minor metabolite.
Nardil is extensively metabolized, primarily by oxidation via monoamine oxidase. After oral administration of (13)C6-phenelzine, 73% of the administered dose was recovered in urine as phenylacetic acid and parahydroxyphenylacetic acid within 96 hours. Acetylation to N2-acetylphenelzine is a minor pathway.
Following ip injection of 2.5 mg/kg bw phenelzine-1-(14)C sulfate to rats, 62% of the dose was recovered in the urine within 24 hours. The major excretion product was phenylacetic acid, which is also a metabolite of phenelzine in mice. The first enzyme involved in this elimination process is monoamine oxidase.
Hepatic. Acetylation of phenelzine appears to be a minor metabolic pathway. Beta-phenylethylamine is a metabolite of phenelzine, and there is indirect evidence that phenelzine may also be ring-hydroxylated and N-methylated.
Route of Elimination: NARDIL® is extensively metabolized, primarily by oxidation via monoamine oxidase.
Half Life: 1.2-11.6 hours following single dose administration. Multiple-dose pharmacokinetics have not been studied.

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Biological Half-Life
After administration phenelzine presents a very short half-life of 11.6 hours in humans.
The mean apparent half-life, estimated from urinary excretion data in patients who received oral doses of 30 mg thrice daily, was 0.87 hours following the initial dose and 3.11 hours after 13 days of treatment.
The mean elimination half-life after a single 30 mg dose is 11.6 hours.

Toxicity Summary
Although the exact mechanism of action has not been determined, it appears that the irreversible, nonselective inhibition of MAO by phenelzine relieves depressive symptoms by causing an increase in the levels of serotonin, norepinephrine, and dopamine in the neuron.

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Hepatotoxicity
Phenelzine, like most monoamine oxidase inhibitors, can cause transient serum aminotransferase elevations in a proportion of patients. These elevations are usually mild, asymptomatic and self-limited and do not require dose modification. Phenelzine has also been associated with cases of acute, clinically apparent liver injury. The liver injury associated with MAO inhibitors typically arises 1 to 3 months after starting therapy and presents with a hepatocellular pattern of serum enzyme elevations. The acute hepatitis-like syndrome can be severe and even fatal. Cholestatic liver injury due to phenelzine has also been described (Case 1). Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. While few cases of phenelzine liver injury have been published, instances of severe jaundice and fatalities due to liver injury have been reported to the FDA and the sponsor.
Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the lack of data on use during breastfeeding, other antidepressants are preferred during breastfeeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Phenelzine can elevate serum prolactin in some patients and has caused galactorrhea in nonpregnant, nonnursing patients. The clinical relevance of these findings in nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Unchanged phenelzine presents a high protein binding which reduced its bioavailability.

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Interactions
MAO inhibitors, including Nardil, are contraindicated in patients receiving guanethidine.
Patients taking Nardil should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of Nardil and spinal anesthesia should be kept in mind. Nardil should be discontinued at least 10 days prior to elective surgery.
The concurrent administration of an MAO inhibitor and bupropion hydrochloride is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion hydrochloride. /MAO inhibitors/
The combination of MAO inhibitors and tryptophan has been reported to cause behavioral and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski signs. /MAO inhibitors/
For more Interactions (Complete) data for Phenelzine (9 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse iv 160 mg/kg body weight
LD50 Mouse oral 160 mg/kg body weight
LD50 Mouse ip 135 mg/kg body weight
LD50 Rat oral 210 mg/kg body weight

[1]. Phenelzine reduces the oxidative damage induced by peroxynitrite in plasma lipids and proteins. Arch Physiol Biochem. 2018 Dec;124(5):418-423.
[2]. Phenelzine, a small organic compound mimicking the functions of cell adhesion molecule L1, promotes functional recovery after mouse spinal cord injury. Restor Neurol Neurosci . 2018;36(4):469-483.

Therapeutic Uses
Antidepressive Agents, Monoamine Oxidase Inhibitors
Phenelzine is used in the treatment of major depressive disorder. /Included in US product label/
Phenelzine has been used with some success in the management of bulimia nervosa. /NOT included in US product label/
Nardil should rarely be the first antidepressant drug used. Rather, it is more suitable for use with patients who have failed to respond to the drugs more commonly used for these conditions.
Nardil has been found to be effective in depressed patients clinically characterized as "atypical," "nonendogenous," or "neurotic." These patients often have mixed anxiety and depression and phobic or hypochondriacal features. There is less conclusive evidence of its usefulness with severely depressed patients with endogenous features.

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Drug Warnings
/BOXED WARNING/ Suicidality and Antidepressant Drugs: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Nardil or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nardil is not approved for use in pediatric patients.
Safety and efficacy of phenelzine in pediatric patients have not been established. The US Food and Drug Administration (FDA) has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders. However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide. Anyone considering the use of phenelzine in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.
Phenelzine shares the toxic potentials of other MAO inhibitors, and the usual precautions and contraindications associated with these drugs should be observed. Patients should be fully advised about the risks, especially hypertensive crisis and suicidal thinking and behavior (suicidality), associated with MAO inhibitor therapy.
Nardil should not be used in patients who are hypersensitive to the drug or its ingredients, with pheochromocytoma, congestive heart failure, severe renal impairment or renal disease, a history of liver disease, or abnormal liver function tests.
For more Drug Warnings (Complete) data for Phenelzine (19 total), please visit the HSDB record page.

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Pharmacodynamics
The elimination of monoamine oxidase by phenelzine results in the elevation of brain amines such as 2-phenylethylamine which is a metabolite of phenelzine. These amines have then marked effects on the uptake and release of catecholamines and serotonin in nerve endings. Phenelzine is shown to elevate brain levels of the gamma-aminobutyric acid (GABA) and alanine (ALA) as well as to inhibit the activity of the transaminases that normally metabolize these amino acids. In preclinical studies, it has been shown to be neuroprotective in cerebral ischemia.

C8H12N2

136.20

136.1

C, 70.55; H, 8.88; N, 20.57

51-71-8

51-71-8; 156-51-4 (sulfate);

3675

Liquid

1.0±0.1 g/cm3

281.4±19.0 °C at 760 mmHg

157-161ºC
Crystals; mp: 174 °C /Phenelzine hydrochloride/
< 25 °C

143.7±25.1 °C

0.0±0.6 mmHg at 25°C

1.550

1.14

2

2

3

10

77.3

0

NNCCC1=CC=CC=C1

RMUCZJUITONUFY-UHFFFAOYSA-N

InChI=1S/C8H12N2/c9-10-7-6-8-4-2-1-3-5-8/h1-5,10H,6-7,9H2

Hydrazine, (2-phenylethyl)-

Phenelzine; 51-71-8; Phenethylhydrazine; 2-Phenylethylhydrazine; Nardil; Fenelzyne; Hydrazine, (2-phenylethyl)-; Fenelzyna;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)