Aspartame is made up of methanol, aspartate, an excitatory neurotransmitter in the central nervous system, and phenylalanine, which is vital for neurotransmitter modulation [2].

Aspartame (4000 mg/kg bw/day; oral) did not cause any negative effects in mice, rats, hamsters, or dogs in acute, subacute, or long-term toxicity investigations of aspartame and its breakdown products[1].

Absorption, Distribution and Excretion
Absorbed in the small intestine, aspartame is metabolized and absorbed very quickly.

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Metabolism / Metabolites
Approximately 10% of aspartame (by weight) is broken down into methanol in the small intestine. Most of the methanol is absorbed and quickly converted into formaldehyde. Approximately 50% of aspartame (by weight) is broken down into phenylalanine. Approximately 40% of aspartame (by mass) is broken down into aspartic acid.
Unlike some other intense sweeteners, aspartame is metabolized in the body and consequently has some nutritive value: 1 g provides approx 17 kJ (4 kcal). However, in practice, the small quantity of aspartame consumed provides a minimal nutritive effect.
The use of aspartame has been of some concern owing to the formation of the potentially toxic metabolites methanol, aspartic acid, and phenylalanine. Of these materials, only phenylalanine is produced in sufficient quantities, at normal aspartame intake levels, to cause concern.
Aspartame [SC-18862; 3-amino-N-(alpha-carboxyphenethyl) succinamic acid, methyl ester, the methyl ester of aspartylphenylalanine] is a sweetening agent that organoleptically has about 180 times the sweetness of sugar. The metabolism of aspartame has been studied in mice, rats, rabbits, dogs, monkeys, and humans. The compound was digested in all species in the same way as are natural constituents of the diet. Hydrolysis of the methyl group by intestinal esterases yielded methanol, which was oxidized in the one-carbon metabolic pool to CO2. The resultant dipeptide was split at the mucosal surface by dipeptidases and the free amino acids were absorbed. The aspartic acid moiety was transformed in large part to CO2 through its entry into the tricarboxylic acid cycle. Phenylalanine was primarily incorporated into body protein either unchanged or as its major metabolite, tyrosine.
Although aspartame was hydrolyzed in the gut of the monkey to its constituent moieties, methanol, aspartic acid, and phenylalanine, the ingestion of 15 or 60 mg/kg doses for 10 days did not modify phenylalanine metabolism. Aspartame had little effect on the disappearance of iv admin (14)C-phenylalanine from the plasma, it did not substantially affect the conversion of phenylalanine into tyrosine or carbon dioxide, and it did not alter the rate of incorporation of label into protein. The majority of phenylalanine derived from aspartame was incorporated into body protein, with only 20-25% of the compound being excreted. 60-80% of the derived methanol and aspartic acid was oxidized to carbon dioxide.
For more Metabolism/Metabolites (Complete) data for Aspartame (7 total), please visit the HSDB record page.

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Biological Half-Life
At room temperature, aspartame is most stable at pH 4.3, where its half-life is nearly 300 days. At pH 7, its half-life is shortened to only a few days.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Aspartame is not detectable in breastmilk after maternal ingestion because it is rapidly broken down in the mother's body. An extremely large intake of aspartame (equivalent to 17 cans of soda or 100 packets of Equal Sweetener) can slightly increase the amount of phenylalanine in breastmilk. Phenylalanine concentrations in milk return to baseline by 12 hours after a large single dose of aspartame. Although it is prudent to avoid the use of aspartame in women who are nursing an infant with phenylketonuria, amounts that are typically ingested in aspartame-sweetened foods and beverages do not result in any additional risk to breastfed infants with phenylketonuria. Ingestion of diet drinks containing low-calorie sweeteners might increase the risk of vomiting in breastfed infants. An association between low-calorie sweeteners, and especially aspartame, and the risk of autism in boys has been found, but more data are needed to establish a cause-and-effect relationship.
◉ Effects in Breastfed Infants
A cross-sectional survey assessed the dietary history of US mothers nursing infants between 11 and 15 weeks of age. The survey was used to estimate the amount of diet soda and fruit drinks consumed by the women. There were no statistically significant differences in infants’ weight or z-scores based on low calorie sweetener exposure. However, infants exposed to low calorie sweetener in milk once or less per week had a statistically significantly higher risk of vomiting than those who were not exposed. Greater exposure was not associated with vomiting. It was not possible to assess the effects of specific sweeteners.
A retrospective dietary recall study compared the use of diet soda and aspartame during pregnancy and/or lactation to the risk of autism in the children. Among boys, autism was associated with three times the likelihood of exposure to aspartame. No statistically significant associations were found in girls. The contribution of exposure during breastfeeding was not separated from the risk of exposure during pregnancy, and intact aspartame is usually not found in milk, so breastmilk exposure cannot be claimed to cause autism based on these data. The authors propose that the methanol metabolite might have an impact on infants.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Interactions
... If mice are given aspartame in doses that elevate plasma phenylalanine levels more than those of tyrosine ... , the frequency of seizures following the administration of an epileptogenic drug, pentylenetetrazole, is enhanced. This effect is simulated by equimolar phenylalanine and blocked by concurrent administration of valine, which blocks phenylalanine's entry into the brain. Aspartame also potentiates the induction of seizures by inhaled fluorothyl or by electroconvulsive shock...
Antimutagenic effects of combination of aspartame (0.4 and 4 mg/kg) and beta-carotene (0.15-15 mg/kg) were studied by estimation of chromosome aberrations in bone marrow cells of C57Bl/6 mice. Single and 5-day treatment with this combination decreased the clastogenic effects of dioxidine and cyclophosphamide and produced a more potent and universal antimutagenic effect than its constituents.
The purpose of the present study was to investigate analgesic and anti-inflammatory properties of aspartame, an artificial sweetener and its combination with various opioids and NSAIDs for a possible synergistic response. The oral administration of aspartame (2-16 mg/kg, po) significantly increased the pain threshold against acetic acid-induced writhes in mice. Co-administration of aspartame (2mg/kg, po) with nimesulide (2 mg/kg, po) and naproxen (5 mg/kg, po) significantly reduced acetic acid-induced writhes as compared to effects per se of individual drugs. Similarly when morphine (1 mg/kg, po) or pentazocine (1 mg/kg, po) was co-administered with aspartame it reduced the number of writhes as compared to their effects per se. Aspartame (4,8,16 mg/kg, po) significantly decreased carrageenan-induced increase in paw volume and also reversed the hyperalgesic effects in rats in combination with nimesulide (2 mg/kg, po). The study indicated that aspartame exerted analgesic and anti-inflammatory effects on its own and have a synergistic analgesic response with conventional analgesics of opioid and non-opioid type, respectively.
Ochratoxin A (OTA) is a mycotoxin produced by Aspergillus ochraceus as well as other molds. This mycotoxin contaminates animal feed and food. OTA is immunosuppressive, genotoxic, teratogenic, carcinogenic and is nephrotoxic in all animal species studied so far. OTA inhibits protein synthesis and induces lipid peroxidation. Since it seems impossible to avoid completely contamination of foodstuffs by toxigenic fungi, it is necessary to investigate the possible ways of limiting such toxicity. An attempt to prevent OTA-induced nephrotoxic and genotoxic effects, mainly the karyomegaly, has been made in vivo using aspartame (L-aspartyl-L-phenylalanine methyl ester), a structural analogue of both OTA and phenylalanine. Aspartame (25 mg/kg bw) prevented most of the nephrotoxic effects induced by OTA (289 ug/kg bw). It also showed some utility in preventing morphological and histological damage, mainly the karyomegaly.
For more Interactions (Complete) data for Aspartame (9 total), please visit the HSDB record page.

[1]. Aspartame: a safety evaluation based on current use levels, regulations, and toxicological and epidemiological studies. Crit Rev Toxicol, 2007. 37(8): p. 629-727.

[2]. Humphries, P., E. Pretorius, and H. Naude, Direct and indirect cellular effects of aspartame on the brain. Eur J Clin Nutr, 2008. 62(4): p. 451-62.

Aspartame is a dipeptide obtained by formal condensation of the alpha-carboxy group of L-aspartic acid with the amino group of methyl L-phenylalaninate. Commonly used as an artificial sweetener. It has a role as a sweetening agent, a nutraceutical, a micronutrient, a xenobiotic, an environmental contaminant, an apoptosis inhibitor and an EC 3.1.3.1 (alkaline phosphatase) inhibitor. It is a dipeptide, a carboxylic acid and a methyl ester. It is functionally related to a L-aspartic acid and a methyl L-phenylalaninate. It is a tautomer of an aspartame zwitterion.
Flavoring agent sweeter than sugar, metabolized as phenylalanine and aspartic acid.
Flavoring agent sweeter than sugar, metabolized as PHENYLALANINE and ASPARTIC ACID.

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Drug Indication
Used as a diet supplement and sugar substitute.

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Mechanism of Action
180 to 200 times sweeter than sucrose, it is metabolized as a protein and its subsequent amino-acids used up in there respective mechanisms.

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Therapeutic Uses
Aspartame is used as an intense sweetening agent ... in pharmaceutical preparations including tablets, powder mixes, and vitamin preparations. It enhances flavor systems and can be used to mask some unpleasant taste characteristics; the approximate sweetening power is 80-200 times that of sucrose.

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Drug Warnings
Aspartame is the methylester of a dipeptide composed of two amino acids, phenylalanine and aspartic acid. ... Persons with phenylketonuria, who must restrict carefully their phenylalanine intake, must be alerted to the presence of phenylalanine in the drug product and the amount of the ingredient in each dosage unit.
Excessive use of aspartame should be avoided by patients with phenylketonuria.
Aspartic acid and sodium glutamate were both neuroexcitatory amino acids which had an additive toxic effect on hypothalamic neurones. As this might be specially damaging to young children, who already receive sodium glutamate in gram quantities in their diet, aspartame should not generally be added to children's food.
Reported adverse effects include: headaches; grand mal seizure; memory loss; gastrointestinal symptoms; and dermatological symptoms. However, scientifically controlled peer-reviewed studies have consistently failed to produce evidence of a causal effect between aspartame consumption and adverse health events ...
For more Drug Warnings (Complete) data for Aspartame (8 total), please visit the HSDB record page.

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Pharmacodynamics
Aspartame (L-alpha-aspartyl-L-phenylalanine methyl ester) is a low-calorie sweetener used to sweeten a wide variety of low- and reduced-calorie foods and beverages, including low-calorie tabletop sweeteners. Aspartame is composed of two amino acids, aspartic acid and phenylalanine, as the methyl ester. Aspartic acid and phenylalanine are also found naturally in protein containing foods, including meats, grains and dairy products. Methyl esters are also found naturally in many foods such as fruits and vegetable and their juices. Upon digestion, aspartame breaks down into three components (aspartic acid, phenylalanine and methanol), which are then absorbed into the blood and used in normal body processes. Neither aspartame nor its components accumulates in the body. These components are used in the body in the same ways as when they are derived from common foods.

C14H18N2O5

294.3

294.121

22839-47-0

Aspartame-d5;1356849-17-6;Aspartame acesulfame;106372-55-8;Aspartame-d3;1356841-28-5

134601

White to off-white solid powder

1.3±0.1 g/cm3

535.8±50.0 °C at 760 mmHg

242-248 °C

277.8±30.1 °C

0.0±1.5 mmHg at 25°C

1.557

1.11

3

6

8

21

380

2

COC(=O)[C@H](CC1=CC=CC=C1)NC(=O)[C@H](CC(=O)O)N

IAOZJIPTCAWIRG-QWRGUYRKSA-N

InChI=1S/C14H18N2O5/c1-21-14(20)11(7-9-5-3-2-4-6-9)16-13(19)10(15)8-12(17)18/h2-6,10-11H,7-8,15H2,1H3,(H,16,19)(H,17,18)/t10-,11-/m0/s1

(3S)-3-Amino-4-[[(2S)-1-methoxy-1-oxo-3-phenylpropan-2-yl]amino]-4-oxobutanoic acid

Nutrasweet Asp-phe-ome AspartamAsp-Phe methyl ester

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~25 mg/mL (~84.95 mM)
H2O : ~5 mg/mL (~16.99 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (8.49 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (8.49 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
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.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (8.49 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 18.33 mg/mL (62.28 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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