Absorption, Distribution and Excretion
Upon oral and IP administration of radioactive malic acid to rats, most of the radioactivity was excreted as carbon dioxide.

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Metabolism / Metabolites
Acidulents. Like l-(14)C4 malic acid, dl-(14)C4 malic acid, when admin ip or orally to rats was extensively metabolized; 90-95% of (14)C was excreted through lungs as (14)CO2. ... Metabolized at same rate irrespective of route admin ... . /L- & dl-malic acid/
Malic acid is an intermediate in the citric acid cycle. It is formed from fumaric acid and is oxidized to oxaloacetic acid. It is also metabolized to pyruvic acid by malic enzyme which is present in many biologic systems, including bacteria and plants. L-Malic and dl-malic acid are both rapidly metabolized in the rat. Orally or ip administered l- or dl-malic acid was extensively eliminated as carbon dioxide (83 to 92%). No differences between the two forms were found in the rates (90 to 95% in 24 hr) or routes of excretion.
Malates are normal constituents of the diet of humans and animals and, when ingested, are rapidly and completely metabolized to CO2. /Malates/
... Both enantiomers of malic acid are readily metabolised by laboratory animals and humans and that there was no reason to distinguish between L-malic acid and DL-malic acid when considering their safe use in food.
Upon oral and IP administration of radioactive Malic Acid to rats, most of the radioactivity was excreted as carbon dioxide.

Toxicity Summary
IDENTIFICATION AND USE: Malic acid forms colorless crystals with a characteristic sour taste. It is used as a cosmetic and food ingredient. Malic acid has been tested as experimental therapy for various conditions. HUMAN EXPOSURE AND TOXICITY: Malic acid and its salts are considered as strongly irritant to the skin and mucosa and as a particular risk to the eyes. Exposure via inhalation for those handling the additives is also considered to present a risk. Malic acid was irritating in clinical tests, with less irritation seen as pH of the applied material increased. Patients patch tested with malic acid, placed on a diet that avoided foods containing malic or citric acid, and then challenged with a diet high in malic and citric acid had both immediate urticarial and delayed contact dermatitis reactions. In the absence of data on inhalation toxicity, inhalation of the malate additive should be considered as hazardous. Because of the particle size distribution of the additives and the high dusting potential of the malate salts, it is likely that handling the additives could result in a production of respirable dust that could present a risk to unprotected workers. ANIMAL STUDIES: Malic acid is a component of the Kreb's cycle. Malic acid was relatively nontoxic in acute toxicity studies using animals. In a chronic oral study, feeding malic acid to rats resulted only in weight gain changes and changes in feed consumption. Malic acid did not cause reproductive toxicity in mice, rats, or rabbits. Malic acid was a moderate to strong skin irritatant in animal tests, and was a strong ocular irritant. Malic acid was not mutagenic across a range of genotoxicity tests.

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Interactions
The influence of some frequent dietary constituents on gastrointestinal absorption of aluminum from drinking water and diet was investigated in mice. Eight groups of male mice received lactic (57.6 mg/kg/day), tartaric (96 mg/kg/day), gluconic (125.4 mg/kg/day), malic (85.8 mg/kg/day), succinic (75.6 mg/kg/day), ascorbic (112.6 mg/kg/day), citric (124 mg/kg/day), and oxalic (80.6 mg/kg/day) acids in the drinking water for one month. At the end of this period, animals were killed and aluminum concentrations in liver, spleen, kidney, brain, and bone were determined. All the dietary constituents significantly increased the aluminum levels in bone, whereas brain aluminum concentrations were also raised by the intake of lactic, gluconic, malic, citric, and oxalic acids. The levels of aluminum found in spleen were significantly increased by gluconic and ascorbic acids, whereas gluconic and oxalic acids also raised the concentrations of aluminum found in kidneys.
The interactions of aqueous solutions of chlorine with some fruit acids (citric acid, DL-malic acid, and L-tartaric acid) different pH values were studied diethyl ether extraction followed by GC/MS analysis indicated that a number of mutagens certain chlorinated propanones and chloral hydrate) are present as major products in some of these samples. A number of fruit juices (orange, grape, apple, pineapple, and grapefruit) were also treated with aqueous solutions of chlorine at their pH values. The products were analyzed by GC/MS. The same mutagens that were formed by the pure acids (citric acid and DL-malic acid) were identified as major products in ether extracts of these samples. All of the major products observed in the chlorination of all five fruit juices are potentially derived from reactions aqueous solutions of chlorine with citric or malic acid and with trace amounts of acetaldehyde and acetone in the juices.
The relative efficacy of citric, malic, malonic, oxalic and succinic acids, and deferoxamine mesylate (DFOA) on the toxicity, distribution and excretion in mice exposed to aluminum were compared. To determine the effect of the various chelators on the toxicity of aluminum various doses of aluminum nitrate (938-3l88 mg/kg) were administered intraperitoneally, followed by one of the chelators. Survival was recorded at the end of 14 days. Malic and succinic acids were the most effective. Malic and succinic acids were the most effective in increasing the urinary excretion of aluminum.
Eight groups of female Sprague-Dawley rats were treated with 281 mg aluminum hydroxide/kg/day by gastric intubation five times a week for fives weeks. Concurrently, animals in seven groups received 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 mq/kg/day), and tartaric acid (48 mg/kg/day) in the drinking water. The eighth group did not receive any dietary constituent in the water and was designated as the control group. Animals were placed in plastic metabolic cages and urine was collected during the treatment period. The liver, spleen, kidney, brain and bone aluminum levels of each rat were measured, as well as the total amount of aluminun excreted into urine. All the dietary constituents significantly increased the aluminum concentrations in most of the tissues, with ascorbic and citric acids showing the highest rate of aluminum accumulation.

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Non-Human Toxicity Values
LD50 Mouse oral 1600-3200 mg/kg
LD50 Mouse ip 50-100 mg/kg
LD50 Rat oral greater than 3200 mg/kg
LD50 Rat ip 100-200 mg/kg
LD50 Rabbit oral 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 that is succinic acid in which one of the hydrogens attached to a carbon is replaced by a hydroxy group. It has a role as a food acidity regulator and a fundamental metabolite. It is a 2-hydroxydicarboxylic acid and a C4-dicarboxylic acid. It is functionally related to a succinic acid. It is a conjugate acid of a malate(2-) and a malate.
Malic acid has been used in trials studying the treatment of Xerostomia, Depression, and Hypertension.
Malic acid has been reported in Camellia sinensis, Solanum tuberosum, and other organisms with data available.
See also: Hibiscus sabdariffa Flower (part of) ... View More ...

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Therapeutic Uses
EXPL THER An efficcacy and safety test of a tablet containing 200 mg malic acid (and 50 mg magnesium) was conducted using patients with primary fibromyalgia syndrome. In the first part of the test, 24 patients were given three tablets twice daily (bid) for 4 weeks. In the second part, 16 patients started with three tablets bid and increased the dosage every 3 to 5 days as necessary; at month 6, the average dose was 8.8 tablets per day. (For a 50-kg person, ingestion of six tablets would be equivalent to 24 mg of malate/kg of body weight). In the first part of the study, one test patient reported diarrhea, one reported nausea, and one reported dyspepsia. (In the placebo group, two patients reported diarrhea and one reported dyspepsia.) In the second part of the study, five test patients reported diarrhea, one reported nausea, one reported dyspepsia, one reported panic attacks, and one reported dizziness.
EXPL THER Organic acids in Chinese herbs, the long-neglected components, have been reported to possess antioxidant, anti-inflammatory, and antiplatelet aggregation activities; thus they may have potentially protective effect on ischemic heart disease. Therefore, this study aims to investigate the protective effects of two organic acids, that is, citric acid and L-malic acid, which are the main components of Fructus Choerospondiatis, on myocardial ischemia/reperfusion injury and the underlying mechanisms. In in vivo rat model of myocardial ischemia/reperfusion injury, we found that treatments with citric acid and L-malic acid significantly reduced myocardial infarct size, serum levels of TNF-alpha, and platelet aggregation. In vitro experiments revealed that both citric acid and L-malic acid significantly reduced LDH release, decreased apoptotic rate, downregulated the expression of cleaved caspase-3, and upregulated the expression of phosphorylated Akt in primary neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation injury. These results suggest that both citric acid and L-malic acid have protective effects on myocardial ischemia/reperfusion injury; the underlying mechanism may be related to their anti-inflammatory, antiplatelet aggregation and direct cardiomyocyte protective effects. These results also demonstrate that organic acids, besides flavonoids, may also be the major active ingredient of Fructus Choerospondiatis responsible for its cardioprotective effects and should be attached great importance in the therapy of ischemic heart disease. /L-Malic Acid/
EXPL THER Objectives: Assessing the clinical effectiveness of a topical sialogogue on spray (malic acid, 1%) in the treatment of xerostomia induced by antihypertensive drugs. Study Design: This research has been carried out through a randomized double-blind clinical trial. 45 patients suffering from hypertensive drugs-induced xerostomia were divided into 2 groups: the first group (25 patients) received a topical sialogogue on spray (malic acid, 1%) whereas the second group (20 patients) received a placebo. Both of them were administered on demand for 2 weeks. Dry Mouth Questionnaire (DMQ) was used in order to evaluate xerostomia levels before and after product/placebo application. Unstimulated and stimulated salivary flows rates, before and after application, were measured. All the statistical analyses were performed by using SPSS software v17.0. Different DMQ scores at the earliest and final stage of the trial were analysed by using Mann-Whitney U test, whereas Student's T-test was used to analyse salivary flows. Critical p-value was established at p<0.05. Results: DMQ scores increased significantly (clinical recovery) from 1.21 to 3.36 points (p<0.05) after malic acid (1%) application whereas DMQ scores increased from 1.18 to 1.34 points (p>0.05) after placebo application. After two weeks of treatment with malic acid, unstimulated salivary flow increased from 0.17 to 0.242 mL/min whereas the stimulated one increased from 0.66 to 0.92 mL/min (p<0.05). After placebo application unstimulated flow ranged from 0.152 to 0.146 mL/min and stimulated flow increased from 0.67 to 0.70 mL/min (p>0.05). Conclusions: Malic acid 1% spray improved antihypertensive-induced xerostomia and stimulated the production of saliva.
Fourteen patients, 11 males and 3 females, with various forms of ichthyosiformdermatoses were used to evaluate the therapeutic potential of more than 60 chemicals, including malic acid. Malic acid was dissolved in either water or ethanol and incorporated into a hydrophilic ointment of plain petrolatum. The ointment, containing 5% malic acid (pH not specified), was applied twice daily to the appropriate test site for 2 weeks. Daily to weekly observations were made. Malic acid provided 3+ (disappearance of scales from lesions) or 4+ (restoration to normal looking skin) improvement in all patients except one with epidermolytic hyperkeratosis.

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.)