Absorption, Distribution and Excretion
Following oral and intraperitoneal injection of radioactive malic acid in rats, most of the radioactive material was excreted as carbon dioxide. Metabolism/Metabolites Acids. Similar to L-(14)C4 malic acid, DL-(14)C4 malic acid is extensively metabolized in rats after intraperitoneal or oral administration; 90-95% of the (14)C is excreted via the lungs as (14)CO2. …The metabolic rate is independent of the route of administration…. /L- and DL-malic Acids/
Malic acid is an intermediate product of the citric acid cycle. It is generated from fumaric acid and oxidized to oxaloacetic acid. It can also be metabolized to pyruvate by malic acidase, an enzyme present in many biological systems, including bacteria and plants. Both L-malic acid and DL-malic acid are rapidly metabolized in rats. Following oral or intraperitoneal injection of L-malic acid or DL-malic acid, most of it is excreted as carbon dioxide (83% to 92%). There was no difference in the excretion rate (90% to 95% within 24 hours) or the route of excretion between the two forms. Malate is a normal component of human and animal diets and is rapidly and completely metabolized into carbon dioxide after ingestion. Both enantiomers of malic acid are rapidly metabolized in experimental animals and humans; therefore, it is not necessary to distinguish between L-malate and DL-malate when considering their safe use in food. After oral and intraperitoneal injection of radiolabeled malic acid into rats, most of the radioactive material was excreted as carbon dioxide.

Toxicity Summary
Identification and Uses: Malic acid forms colorless crystals and has a characteristic sour taste. It is used as a cosmetic and food ingredient. Malic acid has been tested for the treatment of various diseases. Human Exposure and Toxicity: Malic acid and its salts are considered highly irritating to the skin and mucous membranes, especially the eyes. Inhalation exposure is also considered a risk for those who come into contact with the additives. Clinical trials have shown that malic acid is irritating, with irritation decreasing as the pH of the applied substance increases. Patients who received malic acid patch tests, after avoiding a diet containing malic or citric acid, and then receiving a diet high in malic and citric acid, developed immediate urticaria and delayed contact dermatitis. Due to a lack of inhalation toxicity data, inhalation of malic acid additives should be considered harmful. Handling these additives may generate inhalable dust due to the particle size distribution of the additives and the high dust generation potential of malic acid salts, posing a risk to unprotected workers. Animal Studies: Malic acid is a component of the Kjeldahl cycle. In acute toxicity studies in animals, the toxicity of malic acid was relatively low. In chronic oral administration studies, feeding rats with malic acid resulted only in weight gain and changes in food intake. Malic acid showed no reproductive toxicity in mice, rats, or rabbits. Animal studies indicated that malic acid has moderate to severe skin irritation and strong eye irritation. In a series of genotoxicity tests, malic acid did not show mutagenicity.

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Interactions
This study investigated the gastrointestinal effects of several common dietary components on aluminum absorption from drinking water and diet in mice. Eight groups of male mice were given drinking water supplemented with lactic acid (57.6 mg/kg/day), tartaric acid (96 mg/kg/day), gluconic acid (125.4 mg/kg/day), malic acid (85.8 mg/kg/day), succinic acid (75.6 mg/kg/day), ascorbic acid (112.6 mg/kg/day), citric acid (124 mg/kg/day), and oxalic acid (80.6 mg/kg/day) for one month. One month later, mice were sacrificed, and aluminum concentrations in the liver, spleen, kidneys, brain, and bones were measured. All dietary components significantly increased aluminum content in bones, while the intake of lactic acid, gluconic acid, malic acid, citric acid, and oxalic acid also increased aluminum concentration in the brain. Glucolic acid and ascorbic acid significantly increased aluminum content in the spleen, while gluconic acid and oxalic acid also increased aluminum concentration in the kidneys. The interaction between chlorinated aqueous solutions and certain fruit acids (citric acid, DL-malic acid, and L-tartaric acid) at different pH values was investigated. Ether extraction and GC/MS analysis revealed the presence of several major products in some samples, including various mutagens such as chloroacetone and chloral hydrate. Furthermore, various fruit juices (orange, grape, apple, pineapple, and grapefruit juices) were treated with chlorinated aqueous solutions at different pH values, and the products were analyzed by GC/MS. The results showed that the same mutagens produced by pure acids (citric acid and DL-malic acid) were also major products of the ether extracts of these samples. All major products observed during the chlorination of the five fruit juices likely originated from the reaction of chlorinated water with citric or malic acid, as well as trace amounts of acetaldehyde and acetone in the juices. This study compared the relative potency of citric acid, malic acid, malonic acid, oxalic acid, succinic acid, and deferoxamine mesylate (DFOA) in mice exposed to aluminum, considering their toxicity, distribution, and excretion. To determine the effects of various chelating agents on aluminum toxicity, different doses of aluminum nitrate (938–3188 mg/kg) were administered intraperitoneally, followed by an injection of one of the chelating agents. Survival rates were recorded after 14 days. The results showed that malic acid and succinic acid had the best chelating effects. Malic acid and succinic acid were most effective in increasing urinary aluminum excretion. Eight groups of female Sprague-Dawley rats were administered 281 mg/kg aluminum hydroxide daily via gastric tube instillation five times a week for five weeks. Meanwhile, seven groups of animals had their drinking water supplemented with ascorbic acid (56.3 mg/kg/day), citric acid (62 mg/kg/day), gluconic acid (62.7 mg/kg/day), lactic acid (28.8 mg/kg/day), malic acid (42.9 mg/kg/day), oxalic acid (28.8 mg/kg/day), and tartaric acid (48 mg/kg/day), respectively. An eighth group of animals served as a control group without any added nutrients in their drinking water. All animals were placed in plastic metabolic cages, and urine was collected during the treatment period. The aluminum content in the liver, spleen, kidneys, brain, and bones of each rat, as well as the total aluminum excreted in urine, were determined. All dietary components significantly increased aluminum concentrations in most tissues, with ascorbic acid and citric acid showing the highest aluminum accumulation rates.

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Non-human toxicity values
Mice oral LD50: 1600-3200 mg/kg
Mice intraperitoneal LD50: 50-100 mg/kg
Rat oral LD50: >3200 mg/kg
Rat intraperitoneal LD50: 100-200 mg/kg
Rabbit oral LD50: 3000 mg/kg

[1]. Current advance in biological production of malic acid using wild type and metabolic engineered strains. Bioresour Technol. 2018 Jun;258:345-353.

Malic acid is a 2-hydroxydicarboxylic acid, a derivative of succinic acid, in which a hydrogen atom on one carbon atom is replaced by a hydroxyl group. It functions as a food acidity regulator and an important metabolite. Malic acid is a 2-hydroxydicarboxylic acid, and also a C4 dicarboxylic acid. It is functionally related to succinic acid. It is the conjugate acid of malate (2-) and malic acid. Malic acid has been used in research trials for the treatment of xerostomia, depression, and hypertension. Malic acid has been reported to be found in tea trees, potatoes, and other organisms with relevant data. See also: Roselle (partial)... See more...

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Therapeutic Uses
Exploring Treatment: A trial of the efficacy and safety of tablets containing 200 mg of malic acid (and 50 mg of magnesium) in patients with primary fibromyalgia syndrome. In the first part of the trial, 24 patients took three tablets twice daily (bid) for four weeks. In Part II, 16 patients initially took three tablets twice daily (bid), increasing the dose every 3 to 5 days as needed; by the 6th month, the average dose was 8.8 tablets daily. (For a person weighing 50 kg, taking six tablets is equivalent to an intake of 24 mg malic acid per kg of body weight.) In Part I of the study, one subject reported diarrhea, one reported nausea, and one reported indigestion. (Two patients in the placebo group reported diarrhea, and one reported indigestion.) In Part II of the study, five subjects reported diarrhea, one reported nausea, one reported indigestion, one reported panic attacks, and one reported dizziness.
Exploring Treatment: Organic acids in traditional Chinese medicine, these long-neglected components, have been reported to possess antioxidant, anti-inflammatory, and antiplatelet aggregation activities; therefore, they may have potential protective effects against ischemic heart disease. Therefore, this study aims to investigate the protective effects and potential mechanisms of two organic acids—citric acid and L-malic acid (both major components of Poria cocos fruit)—on myocardial ischemia/reperfusion injury. In a rat model of myocardial ischemia/reperfusion injury, we found that both citric acid and L-malic acid treatment significantly reduced myocardial infarction area, serum TNF-α levels, and platelet aggregation. In vitro experiments showed that both citric acid and L-malic acid significantly reduced LDH release and apoptosis rate in hypoxic/reoxygenated neonatal rat primary cardiomyocytes, downregulated cleaved caspase-3 expression, and upregulated phosphorylated Akt expression. These results suggest that both citric acid and L-malic acid have a protective effect against myocardial ischemia/reperfusion injury. Their potential mechanism may be related to their anti-inflammatory, anti-platelet aggregation, and direct cardiomyocyte protective effects. These results also indicate that, in addition to flavonoids, organic acids may also be the main active components of Tribulus terrestris fruit, responsible for its cardioprotective effect, and should be given high priority in the treatment of ischemic heart disease. /L-malic acid/
Exploratory treatment objective: To evaluate the clinical efficacy of a local salivary spray (1% malic acid) in treating drug-induced xerostomia. Study design: This study employed a randomized, double-blind clinical trial design. Forty-five patients with drug-induced dry mouth were randomly assigned to two groups: Group 1 (n=25) received a topical salivary spray (1% malic acid), and Group 2 (n=20) received a placebo. Both groups received medication as needed for two weeks. The Dry Mouth Questionnaire (DMQ) was used to assess the severity of dry mouth symptoms before and after product/placebo use. Non-irritating and irritating salivary flow rates were measured before and after product/placebo use. All statistical analyses were performed using SPSS version 17.0. The Mann-Whitney U test was used to analyze different DMQ scores at the early and late stages of the trial, while Student's t-test was used to analyze salivary flow rates. A significance level was set at p<0.05. Results: After application of 1% malic acid, the DMQ score significantly increased (clinical recovery), from 1.21 to 3.36 (p<0.05); while after placebo treatment, the DMQ score only increased from 1.18 to 1.34 (p>0.05). After two weeks of malic acid treatment, the non-irritating saliva flow rate increased from 0.17 mL/min to 0.242 mL/min, while the irritating saliva flow rate increased from 0.66 mL/min to 0.92 mL/min (p<0.05). After placebo treatment, the non-irritating saliva flow rate ranged from 0.152 mL/min to 0.146 mL/min, and the irritating saliva flow rate increased from 0.67 mL/min to 0.70 mL/min (p>0.05). Conclusion: 1% malic acid spray can improve dry mouth induced by antihypertensive drugs and stimulate saliva secretion. This study included 14 patients (11 men and 3 women) with different types of ichthyosis-like skin diseases to evaluate the therapeutic potential of more than 60 chemicals, including malic acid. Malic acid was dissolved in water or ethanol and added to a hydrophilic petroleum jelly ointment. This ointment contained 5% malic acid (pH unspecified) and was applied twice daily to the corresponding test sites for 2 weeks. Patients were observed daily or weekly. Except for one patient with epidermolytic hyperkeratosis, all patients achieved a 3+ (disappearance of scales) or 4+ (restoration of normal skin appearance) improvement after using malic acid.

C4H6O5

134.0874

134.021

6915-15-7

78644-42-5;676-46-0 (di-hydrochloride salt)

525

White to off-white solid powder

1.6±0.1 g/cm3

306.4±27.0 °C at 760 mmHg

131-133ºC(lit.)

153.4±20.2 °C

0.0±1.5 mmHg at 25°C

1.529

-1.26

3

5

3

9

129

0

BJEPYKJPYRNKOW-UHFFFAOYSA-N

InChI=1S/C4H6O5/c5-2(4(8)9)1-3(6)7/h2,5H,1H2,(H,6,7)(H,8,9)

2-hydroxybutanedioic acid

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)

DMSO : ~100 mg/mL (~745.77 mM)
H2O : ~100 mg/mL (~745.77 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (15.51 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 20.8 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: ≥ 2.08 mg/mL (15.51 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 20.8 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: ≥ 2.08 mg/mL (15.51 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 110 mg/mL (820.34 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.)