The primary targets of DL-mannitol are osmotic gradients in the body. As an osmotic diuretic, it increases osmotic pressure in the renal tubules, preventing water reabsorption and promoting diuresis. It may also play a role in reducing off-target 68Ga-PSMA renal uptake. Its anti-arrhythmic properties suggest additional cardiovascular targets.

D-mannitol and a sample of L-mannitol produced by reducing L-mannono-1, Clactone are combined to create DL-mannitol[1].

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In vitro studies demonstrate that DL-mannitol is obtained by combining D-mannitol with L-mannitol obtained by reduction of L-mannono-1,4-lactone. It has a very low reabsorption rate in renal tubules and is considered impermeable to them. The compound's high hydrophilicity limits its ability to cross cell membranes, which is consistent with its role as an osmotic agent.

In vivo studies show that DL-mannitol acts as an osmotic diuretic and presents anti-arrhythmic properties in anesthetized rat models of ventricular fibrillation and tachycardia induced by ischemia-reperfusion. Approximately 7% of ingested mannitol is absorbed during gastrointestinal instillation. It is used in research on cerebral edema and glaucoma. The compound may play a role in reducing off-target 68Ga-PSMA renal uptake.

Non-cellular assays for DL-mannitol typically involve measuring its osmotic properties. The compound's ability to increase osmotic pressure is measured using osmometers. Its antioxidant activity as an AOS scavenger can be assessed using cell-free antioxidant assays. The compound's physical properties, including its high water solubility and stability, are characterized using standard analytical techniques.

Cellular assays for DL-mannitol are limited, as the compound's mechanism of action is primarily osmotic rather than receptor-mediated. It may be used in cell culture media as an osmotic agent or cryoprotectant. Its effects on cell volume and osmolarity can be studied in various cell types. The compound's low membrane permeability makes it suitable for studying osmotic effects without cellular uptake.

In vivo animal experiments for DL-mannitol typically use rat models. In one protocol, the compound is administered to anesthetized rats to study its anti-arrhythmic properties in models of ventricular fibrillation and tachycardia induced by ischemia-reperfusion. The compound is also used in models of cerebral edema and glaucoma to assess its osmotic diuretic effects. Dosages and routes of administration vary depending on the experimental model.

Absorption, Distribution and Excretion
In uremic patients, approximately 7% of ingested mannitol is absorbed during gastrointestinal instillation. Following inhalation of 635 mg mannitol powder, the peak plasma concentration (Cmax) reaches 13.71 μg/mL (Tmax) within 1.5 hours, with a mean systemic AUC of 73.15 μg·h/mL. Mannitol is primarily excreted unchanged in the urine. In healthy volunteers, after oral inhalation of 635 mg mannitol, 55% of the total dose was excreted unchanged in the urine; after oral or intravenous administration of 500 mg mannitol, the corresponding absorption rates were 54% and 87%, respectively. The volume of distribution for intravenously administered mannitol is 34.3 L. The total clearance of intravenously administered mannitol is 5.1 L/hr, and the renal clearance is 4.4 L/hr. Mannitol is generally considered not to be absorbed from the gastrointestinal tract. However, recent studies contradict this view, as 18% of orally administered D-(14)C mannitol was recovered in the urine of human subjects within 48 hours without change; within 12 hours, up to 19% of mannitol was present in exhaled air as carbon dioxide. 32% of the unabsorbed substance was found in feces within 48 hours. The apparent volume of distribution of certain substances (such as mannitol) corresponds to the total extracellular fluid (approximately 20% of body weight), and they can penetrate capillary membranes but not cell membranes. Mannitol has an extremely low reabsorption rate, and in many practical applications, the renal tubules can be considered impermeable to it. …Osmotic diuretics, as the name suggests, have a very low reabsorption rate in the renal tubules and therefore cannot be absorbed from the gastrointestinal tract. …These drugs must be administered via the parenteral route… to achieve effective plasma concentrations. Mannitol is hardly metabolized to glycogen in the liver.
...Polyhydroxy sugar alcohols...Mannitol (C6H14O6)...is mainly excreted unchanged in the urine.
Mannitol is abundant in Aspergillus oryzae spores and is rapidly metabolized in the early stages of germination. D-mannitol dehydrogenase converts it to fructose...
...After absorption from the digestive tract, the metabolic pathway of mannitol in animals (monkeys, rabbits, rats, dogs, etc.) includes: a small amount is converted into glycogen in the liver, and the remainder is excreted unchanged in the urine.

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Biological half-life
The elimination half-life of orally administered mannitol is 4.7 hours; the mean terminal elimination half-life is similar regardless of the route of administration (oral, inhalation, and intravenous).

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Pharmacokinetic studies show that approximately 7% of ingested DL-mannitol is absorbed during gastrointestinal instillation. The compound has an extremely low reabsorption rate, and renal tubules are considered impermeable to it. As an osmotic diuretic, it is excreted unchanged in the urine. Its high water solubility and low membrane permeability contribute to its limited oral bioavailability.

Interactions
Hydroxyurea (HU) is a potent mammalian teratogen. Within 2-4 hours of maternal injection, HU causes: 1) rapid embryonic cell death; 2) significant inhibition of embryonic DNA synthesis. Various antioxidants can delay embryonic cell death and reduce the incidence of birth defects. Antioxidants do not block the inhibition of DNA synthesis, suggesting that early embryonic cell death is not caused by DNA synthesis inhibition. We hypothesize that certain HU molecules may react within the embryo, generating H₂O₂ and subsequent free radicals, including highly reactive hydroxyl radicals. These free radicals may lead to early cell death; antioxidants are thought to terminate abnormal free radical reactions, thereby mitigating developmental toxicity. To investigate whether hydroxyl radicals cause early cell death, researchers subcutaneously injected pregnant New Zealand white rabbits with a teratogenic dose of hydroxyurea (HU, 650 mg/kg) on day 12 of gestation, with or without the addition of 550 mg/kg of D-mannitol (Man, a hydroxyl radical-specific scavenger). Rabbits in the osmolarity control group were injected with HU, along with 550 mg/kg of xylose (Xyl, an inactive aldose). At full term, Man (HU) mitigated the teratogenic effects of HU, manifested as a reduced incidence of expected limb deformities. Xyl had no significant effect on the teratogenic effects of HU. Histological examination of limb buds in female rabbits 3-8 hours after injection revealed that Man delayed HU-induced cell death by up to 4 hours. Xyl had no such effect. To demonstrate the role of mannitol (Man) in the embryo, researchers administered intraperitoneal injections (mannitol, xylitol, or saline) at different implantation sites, followed by subcutaneous injections of hydroxyurea (HU) into pregnant ewes. Embryos were retrieved 3-8 hours later. The limb buds of embryos injected with saline and xylitol showed a typical pattern of widespread HU-induced cell death within 3-4 hours, while the embryos injected with mannitol showed cell death 5-8 hours later. These results are consistent with reports of antioxidant-mediated mitigation of HU-induced developmental toxicity and the hypothesis that hydroxyl radicals are the main active substances in HU-induced early embryonic cell death. ...Pentobarbital can alleviate blood-brain barrier disruption induced by hypertonic mannitol. This may be at least partly attributed to the hypotensive effect of pentobarbital. Significance: When the blood-brain barrier (BBB) is disrupted by hypertonic solutions, pentobarbital can reduce the degree of BBB leakage. The systemic hypotension induced by pentobarbital plays an important role in reducing leakage. Our study suggests that pentobarbital may effectively protect the BBB when it is disrupted. Furthermore, systemic blood pressure plays a crucial role in determining the degree of BBB disruption.

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Non-human toxicity values
Oral LD50 in rats: 13,500 mg/kg
Intravenous LD50 in rats: 9690 mg/kg
Oral LD50 in mice: 22 g/kg
Intraperitoneal LD50 in mice: 14 g/kg
Intravenous LD50 in mice: 7470 mg/kg

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Toxicological data for DL-mannitol indicate that it is generally recognized as safe for use as a food additive and pharmaceutical excipient. The compound has notable stability and is considered non-toxic at typical doses. High doses may cause osmotic diarrhea and dehydration due to its osmotic effects in the gastrointestinal tract. Standard laboratory safety precautions should be followed when handling the compound.

[1]. Towards understanding 13C-N.M.R. chemical shifts of carbohydrates in the solid state. The spectra of d-mannitol polymorphs and of dl-mannitol. Carbohydrate Research, 197, 41–52.

Therapeutic Uses
Osmotic Diuretic
Medication (Veterinary): Pretreatment with a 10% mannitol solution before aortic angiography can protect the kidneys and reduce the incidence of paraplegia and azotemia in dogs.
Medication (Veterinary): Used in dogs as an osmotic diuretic to induce cellular dehydration, thereby reducing intraocular pressure in patients with glaucoma and alleviating cerebral edema after surgery or injury.
Dosage for reducing intracranial pressure and brain volume before neurosurgery, or for reducing intraocular pressure… For the treatment of congestive glaucoma or ophthalmic surgery, the dosage is 1.5 to 2 g/kg, administered intravenously over 30 to 60 minutes in a 15% or 20% solution.
For more complete data on the therapeutic uses of D-mannitol (15 in total), please visit the HSDB record page.

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Drug Warnings
In edematous conditions with decreased cardiac reserve, the risks of using mannitol may far outweigh any therapeutic benefits.
Contraindications for mannitol include kidney disease, anuria, significant pulmonary congestion or edema, significant dehydration, and intracranial hemorrhage. Bleeding…Mannitol should be discontinued if the patient develops progressive renal impairment, heart failure, or pulmonary congestion.
The safety of mannitol in pregnancy and children under 12 years of age has not been established.
Artificial hypophosphatemia was observed in one patient who received a high-dose intravenous injection of mannitol. Concentrations as low as 25 mmol/L can inhibit the DuPont ACA endpoint assay for phosphorus; kinetics are unaffected. The mannitol interference mechanism is binding to molybdate, leading to a decreased colorimetric rate and a delay in endpoint measurement.
For more complete data on drug warnings for D-mannitol (9 of 9), please visit the HSDB record page.

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Pharmacodynamics
From a chemical perspective, mannitol is an alcohol and sugar, or polyol; it is similar to xylitol or sorbitol. However, mannitol readily loses hydrogen ions in aqueous solutions, making the solution acidic. Therefore, substances such as sodium bicarbonate are usually added to adjust its pH. Mannitol is commonly used to increase urine output (diuretics). It is also used to treat or prevent conditions caused by increased body fluid/water (e.g., cerebral edema, glaucoma, kidney failure). Mannitol is often used in combination with other diuretics (e.g., furosemide, chlorothiazide) and/or intravenous infusions. Inhalation of mannitol may cause bronchospasm and hemoptysis; if any of these occur, inhalation of mannitol should be stopped immediately.

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Other information includes DL-mannitol's use as a sweetener, pharmaceutical excipient (bulking agent), and osmotic diuretic. It is used in research on cerebral edema and glaucoma. The compound may play a role in reducing off-target 68Ga-PSMA renal uptake. It acts as an AOS scavenger and presents anti-arrhythmic properties. DL-mannitol exhibits high solubility in water and is frequently utilized as an osmotic agent.

C6H14O6

182.17

182.079

87-78-5

DL-Mannitol-13C;132144-93-5

6251

White to off-white solid powder

1.596

494.9°C

167°C

292.5±23.3 °C

0.0±2.8 mmHg at 25°C

1.597

-4.67

6

6

5

12

105

4

C([C@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O)O

FBPFZTCFMRRESA-KVTDHHQDSA-N

InChI=1S/C6H14O6/c7-1-3(9)5(11)6(12)4(10)2-8/h3-12H,1-2H2/t3-,4-,5-,6-/m1/s1

(2R,3R,4R,5R)-hexane-1,2,3,4,5,6-hexol

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)

H2O: 62.5 mg/mL (343.09 mM)

Solubility in Formulation 1: 50 mg/mL (274.47 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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