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

Absorption, Distribution and Excretion
Approximately 7% of ingested mannitol is absorbed during gastrointestinal perfusion in uremic patients. Inhalation of 635 mg of mannitol powder yields a plasma Cmax of 13.71 μg/mL in 1.5 hours (Tmax) and a mean systemic AUC of 73.15 μg\*h/mL.
Mannitol is primarily excreted unchanged in the urine. Following oral inhalation of 635 mg of mannitol in healthy volunteers, 55% of the total dose was recovered unchanged in the urine; following oral or intravenous administration of 500 mg, the corresponding values were 54 and 87%, respectively.
Mannitol administered intravenously has a volume of distribution of 34.3 L.
Intravenous administration of mannitol yields a total clearance of 5.1 L/hr and renal clearance of 4.4 L/hr.
MANNITOL IS GENERALLY REGARDED AS BEING UNABSORBED FROM GI TRACT. HOWEVER, RECENT WORK CONTRADICTS THIS BELIEF, FOR 18% OF ORAL DOSE OF D-(14)C MANNITOL WAS RECOVERED UNCHANGED IN 48-HR URINE OF HUMAN SUBJECTS & UP TO 19% AS CO2 IN EXPIRED AIR IN 12 HR. 32% PRESENT IN FECES IN 48 HR...UNABSORBED MATERIAL.
SUBSTANCES /MANNITOL/ HAVING APPARENT VOL OF DISTRIBUTION CORRESPONDING TO TOTAL EXTRACELLUR WATER, WHICH IS ABOUT 20% BODY WT...PENETRATE CAPILLARY MEMBRANES BUT DO NOT PENETRATE CELLULAR MEMBRANES.
MANNITOL UNDERGOES VERY LITTLE REABSORPTION, & FOR MANY PRACTICAL PURPOSES TUBULE MAY BE CONSIDERED TO BE IMPERMEABLE TO IT. ...OSMOTIC DIURETICS, WHICH, BY DEFINITION, ARE POORLY REABSORBED BY RENAL TUBULES, ARE ALSO NOT ABSORBED FROM GI TRACT. ...THESE AGENTS MUST BE ADMIN PARENTERALLY...TO ACHIEVE EFFECTIVE PLASMA CONCN.

---

Metabolism / Metabolites
Mannitol is metabolized only slightly, if at all, to glycogen in the liver.
...POLYHYDRIC SUGAR ALC...MANNITOL (C6H14O6)...LARGELY EXCRETED UNCHANGED IN URINE.
MANNITOL OCCURS IN LARGE AMT IN SPORES OF ASPERGILLUS ORYZAE, WHERE IT IS RAPIDLY METABOLIZED IN EARLY STAGES OF GERMINATION. IT IS CONVERTED TO FRUCTOSE BY D-MANNITOL DEHYDROGENASE...
...FATE OF MANNITOL IN ANIMAL BODY (MONKEYS, RABBITS, RATS, DOGS, ETC) AFTER ABSORPTION FROM DIGESTIVE TRACT INCL LIMITED CONVERSION TO GLYCOGEN IN LIVER & ELIMINATION OF BALANCE UNCHANGED IN URINE.

---

Biological Half-Life
Mannitol has an elimination half-life of 4.7 hours following oral administration; the mean terminal elimination half-life is similar regardless of administration route (oral, inhalation, and intravenous.

Interactions
Hydroxyurea (HU) is a potent mammalian teratogen. Within 2-4 hours after maternal injection, HU causes 1) a rapid episode of embryonic cell death and 2) profound inhibition of embryonic DNA synthesis. A variety of antioxidants delays the onset of embryonic cell death and reduces the incidence of birth defects. Antioxidants do not block the inhibition of DNA synthesis, indicating that early embryonic cell death is not caused by inhibited DNA synthesis. We have suggested that some HU molecules may react within the embryo to produce H2O2 and subsequent free radicals, including the very reactive hydroxyl free radical. The free radicals could cause the early cell death; antioxidants are believed to terminate the aberrant free radical reactions resulting in lessened developmental toxicity. To investigate whether hydroxyl free radicals cause the early episode of cell death, pregnant New Zealand white rabbits were injected subcutaneously on gestational day 12 with a teratogenic dose of HU (650 mg/kg) in the presence or absence of 550 mg/kg of D-mannitol (Man), a specific scavenger of hydroxyl free radicals. Osmotic control rabbits received HU plus 550 mg/kg of xylose (Xyl, a nonactive aldose). At term, the teratologic effects of HU were ameliorated by Man as evidenced by decreased incidences of the expected limb malformations. Xyl exerted no demonstrable effect on HU teratogenesis. Histological examination of limb buds at 3-8 hours after maternal injection, showed that Man delayed the onset of HU-induced cell death by as much as 4 hours. Xyl had no effect. That Man acts within the embryo was shown by performing intracoelomic injections on alternate implantation sites with Man, Xyl, or saline followed by subcutaneous injection of the pregnant doe with HU. Embryos were harvested 3-8 hours later. Limb buds from saline- and Xyl-injected embryos exhibited the typical pattern of widespread HU-induced cell death at 3-4 hours, whereas Man-injected embryos did not exhibit cell death until 5-8 hours. These results are consistent with those reported for antioxidant-mediated amelioration of HU-induced developmental toxicity and with the hypothesis that hydroxyl free radicals are the proximate reactive species in HU-induced early embryonic cell death.
... Pentobarbital attenuated the blood-brain barrier disruption induced by hyperosmolar mannitol. This may be attributed, at least in part, to the blood pressure effect of pentobarbital. Implications: When the blood-brain barrier (BBB) was disrupted by a hyperosmolar solution, pentobarbital attenuated the degree of leakage of the blood-brain barrier. Systemic hypotension caused by pentobarbital played a significant role in decreasing the leakage. Our study suggests that when the blood-brain barrier is disrupted, pentobarbital may be effective in protecting the blood-brain barrier. Furthermore, systemic blood pressure plays an important role in determining the degree of disruption.

---

Non-Human Toxicity Values
LD50 Rat oral 13,500 mg/kg
LD50 Rat iv 9690 mg/kg
LD50 Mouse oral 22 g/kg
LD50 Mouse ip 14 g/kg
LD50 Mouse iv 7470 mg/kg

[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
Diuretics, Osmotic
MEDICATION (VET): INTRAAORTIC PRETREATMENT WITH 10% MANNITOL SOLN PRIOR TO INTRAAORTIC CONTRAST ANGIOGRAPHY PROCEDURES GIVES RENAL PROTECTION & REDUCES INCIDENCE OF PARAPLEGIA & AZOTEMIA IN DOGS.
MEDICATION (VET): IN DOGS AS OSMOTIC DIURETIC CAUSING CELLULAR DEHYDRATION, TO REDUCE INTRAOCULAR PRESSURE IN GLAUCOMA, & TO REDUCE CEREBRAL EDEMA FOLLOWING SURGERY OR INJURY.
DOSE FOR REDUCTION OF INTRACRANIAL PRESSURE & BRAIN MASS PRIOR TO NEUROSURGERY, OR FOR REDUCTION OF INTRAOCULAR TENSION...OF CONGESTIVE GLAUCOMA OR FOR OPHTHALMIC SURGERY, IS 1.5 TO 2 G/KG, GIVEN AS 15 OR 20% SOLN OVER PERIOD OF 30 TO 60 MIN.
For more Therapeutic Uses (Complete) data for D-MANNITOL (15 total), please visit the HSDB record page.

---

Drug Warnings
IN EDEMATOUS STATES ASSOC WITH DIMINISHED CARDIAC RESERVE, ADMIN OF MANNITOL INTRODUCES A RISK THAT MAY FAR OUTWEIGH ANY THERAPEUTIC BENEFIT.
CONTRAINDICATIONS TO ADMIN OF MANNITOL INCL RENAL DISEASE...ANURIA, MARKED PULMONARY CONGESTION OR EDEMA, MARKED DEHYDRATION, & INTRACRANIAL HEMORRHAGE... MANNITOL SHOULD BE TERMINATED IF PATIENTS DEVELOPS...PROGRESSIVE RENAL DYSFUNCTION, HEART FAILURE, OR PULMONARY CONGESTION.
ITS SAFE USE DURING PREGNANCY & IN CHILDREN UNDER 12 YR OF AGE HAS NOT BEEN ESTABLISHED.
FACTITIOUS HYPOPHOSPHATEMIA WAS OBSERVED IN A PATIENT RECEIVING LARGE AMT OF IV MANNITOL. CONCN AS LOW AS 25 MMOL/L INHIBITED PHOSPHORUS MEASUREMENT BY DUPONT ACA ENDPOINT METHOD; A KINETIC METHOD WAS UNAFFECTED. MECHANISM OF MANNITOL INTERFERENCE WAS BINDING TO MOLYBDATE IN REACTION, DECR RATE OF COLOR DEVELOPMENT & ENDPOINT MEASUREMENT.
For more Drug Warnings (Complete) data for D-MANNITOL (9 total), please visit the HSDB record page.

---

Pharmacodynamics
Chemically, mannitol is an alcohol and a sugar, or a polyol; it is similar to xylitol or sorbitol. However, mannitol has a tendency to lose a hydrogen ion in aqueous solutions, which causes the solution to become acidic. For this reason, it is not uncommon to add a substance to adjust its pH, such as sodium bicarbonate. Mannitol is commonly used to increase urine production (diuretic). It is also used to treat or prevent medical conditions that are caused by an increase in body fluids/water (e.g., cerebral edema, glaucoma, kidney failure). Mannitol is frequently given along with other diuretics (e.g., furosemide, chlorothiazide) and/or IV fluid replacement. Inhaled mannitol has the possibility to cause bronchospasm and hemoptysis; the occurrence of either should lead to discontinuation of inhaled mannitol.

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.

---

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