Misoprostol, a PGE2 receptor agonist that is utilized clinically as an anti-ulcer agent and signals through the protective PGE2 EP2, EP3, and EP4 receptors, would reduce brain injury in the murine middle cerebral artery occlusion–reperfusion (MCAO-RP) model. Administration of misoprostol, at the time of MCAO or 2 h after MCAO, resulted in significant rescue of infarct volume at 24 and 72 h. Immunocytochemistry demonstrated dynamic regulation of the EP2 and EP4 receptors during reperfusion in neurons and endothelial cells of cerebral cortex and striatum, with limited expression of EP3 receptor. EP3−/− mice had no significant changes in infarct volume compared to control littermates. Moreover, administration of misoprostol to EP3+/+ and EP3−/− mice showed similar levels of infarct rescue, indicating that misoprostol protection was not mediated through the EP3 receptor. Taken together, these findings suggest a novel function for misoprostol as a protective agent in cerebral ischemia acting via the PGE2 EP2 and/or EP4 receptors.

Subcutaneous injection of misoprostol resulted in significant reductions in infarct size when given at the time of MCAO and 2 h after the onset of MCAO, with comparable protection at 24 and 72 h after MCAO.[1]

Absorption, Distribution and Excretion
For an 800µg oral dose of misoprostol, the AUC was 2.0192±0.8032h\*ng/mL, the Cmax was 2.6830±1.2161ng/mL, and a tmax of 0.345±0.186h. For a 800µg sublingual dose of misoprostol, the AUC was 3.2094±1.0417h\*ng/mL, the Cmax was 2.4391±1.1567ng/mL, and a tmax of 0.712±0.415h. For a 800µg buccal dose of misoprostol, the AUC was 2.0726±0.3578h\*ng/mL, the Cmax was 1.3611±0.3436ng/mL, and a tmax of 1.308±0.624h.
As much as 73.2±4.6% of a radiolabelled oral dose of misoprostol is recovered in the urine.
Data regarding the volume of distribution of misoprostol is scarce. The apparent volume of distribution of the active metabolite of misoprostol was in subjects with normal renal function was 13.6±8.0L/kg, with mild renal impairment was 17.3±23.0L/kg, with moderate renal impairment was 14.3±6.8L/kg, and with end stage renal disease was 11.0±9.6L/kg.
Because of the rapid de-esterification of misoprostol before or during absorption, it is usually undetectable in plasma. Misoprostol's active metabolite, misoprostol acid, has a total body clearance of 0.286L/kg/min. Subjects with mild renal impairment had a total body clearance of 0.226±0.073L/kg/min, subjects with moderate renal impairment had a total body clearance of 0.270±0.103L/kg/min, and subjects with end stage renal disease had a total body clearance of 0.105±0.052L/kg/min.
Rapidly absorbed following oral administration.
Elimination: Renal (64 to 73% of the oral dose excreted within the first 24 hours). Fecal (15% of the oral dose).

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Metabolism / Metabolites
Misoprostol is de-esterified to its active metabolite, misoprostol acid, also known as SC-30695. This metabolite is further reduced to dinor and tetranor metabolites (SC-41411), a prostaglandin F₁ (PGF₁) analog of SC-41411, and a ω-16-carboxylic acid derivative. However, the majority of these metabolites are not well described in the literature.
Rapidly de-esterified to misoprostol acid (primary biologically active metabolite). The de-esterified metabolite undergoes further metabolism by beta and omega oxidation, which can take place in various tissues in the body.

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Biological Half-Life
The half life of an 800µg oral dose is 1.0401±0.5090h, for a sublingual dose is 0.8542±0.1170h, and for a buccal dose is 0.8365±0.1346h.
Terminal - 20-40 minutes

Interactions
Concurrent use /of magnesium-containing antacids/ with misoprostol may aggravate misoprostol induced diarrhea.
This study aimed to investigate the effect of acetaminophen on the hepatic microvasculature using a vascular casting technique. Acetaminophen was admin at a dose of 650 mg/kg body weight (ip) to fasted male Long Evans rats. Microvascular casting was performed at various points after drug admin. Liver casts from control rats showed good patency with normal hepatic microvasculature. Thirty-six hr after overdose with acetaminophen, liver casts showed rounded centrilobular cavities of various sizes, representing regions in which cast-filled sinusoids were absent with relatively normal microvasculature within periportal regions. Evidence of microvascular injury occurred as early as 5 hr after acetaminophen overdose. This injury consisted of changes to centrilobular sinusoids inc areas of incomplete filling and dilated centrilobular sinusoids. Misoprostol ... treatment (6 x 25 ug/kg) given before and after acetaminophen admin markedly reduced the extent of microvascular injury with only small focal unfilled areas in the casts and a generally intact microvasculature. In conclusion, this study shows that overdosage with acetaminophen resulted in an extensive, characteristic pattern of hepatic microvascular injury in the centrilobular region. The results also suggest that microvascular injury is an early event in the pathogenesis of acetaminophen hepatotoxicity. Misoprostol was found to protect against injury occurring at the microvascular level.
Cyclosporin A has markedly improved graft survival in transplant patients but its side effects, such as renal toxicity and hypertension, pose management problems in transplant recipients. This toxicity has been attributed to prostaglandin inhibition. Concurrent admin of misoprostol ... prevents chronic cyclosporin A-induced nephrotoxicity but not hypertension in rats.
The effects of misoprostol on indomethacin-induced decline in renal function were studied in 6 normotensive and 6 hypertensive female patients (mean age 60.5 yr) who were given 25 mg of indomethacin every 6 hr for 3 days, 200 ug of misoprostol every 6 hr for 3 days, and both together for 3 days, with a 4 day washout period between treatments. All patients received a salt-restricted diet, and the hypertensive patients were treated with hydrochlorothiazide. Three of the hypertensive patients and 3 of the normotensive patients had a decr in glomerular filtration rate (GFR) assoc with indomethacin therapy. when misoprostol was given with the indomethacin, 4 of these 6 patients did not experience a decline in GFR. It in concluded that misoprostol ameliorates indomethacin-induced renal dysfunction in salt-restricted and diuretic-treated middle aged women with normal serum creatinine.
Misoprostol ... was given simultaneously with acetylsalicylic acid in a double-blind, placebo-controlled randomized prospective study of 32 healthy human male subjects. Fecal blood loss was measured for 8 days ... Aspirin (650 mg qid) and misoprostol (25 ug qid) or placebo were given during days 3, 4, and 5. there was a significant (P < 0.05) incr in median blood loss ... from 0.81 to 6.05 ml/day in the aspirin with placebo group (n=16). Median blood loss was incr (from 0.75 to 3.75 ml/day)in the aspirin with misoprostol group (n=16), but this was significantly less ... than the placebo group. Mean serum salicylate concn in the placebo and misoprostol groups were similar (7.8 and 6.8 ug/ml, respectively). There were no significant changes in laboratory values in any of the subjects studied, nor were any major side-effects encountered. This study demonstrates that oral misoprostol reduced aspirin-induced GI bleeding even when admin simultaneously and at a dose level below its threshold for significant acid inhibition. This indicates a potential role for misoprostol in the prevention of gastric mucosal damage in selected patients.

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Non-Human Toxicity Values
LD50 Rat oral 81-100 mg/kg
LD50 Mouse oral 27-138 mg/kg
LD50 Rat ip 40-62 mg/kg
LD50 Mouse ip 70-160 mg/kg

[1]. Neurosci Lett . 2008 Jun 20;438(2):210-5.

Misoprostol can cause developmental toxicity according to state or federal government labeling requirements.
7-[(1R,2R,3R)-3-hydroxy-2-(4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopentyl]heptanoic acid methyl ester is a prostanoid.
Misoprostol is a prostaglandin analog used to reduce the risk of NSAID related ulcers, manage miscarriages, prevent post partum hemorrhage, and also for first trimester abortions. The stimulation of prostaglandin receptors in the stomach reduces gastric acid secretion, while stimulating these receptors in the uterus and cervix can increase the strength and frequency of contractions and decrease cervical tone. Misoprostol was granted FDA approval on 27 December 1988.
Misoprostol is a Prostaglandin E1 Analog.
A synthetic analog of natural prostaglandin E1. It produces a dose-related inhibition of gastric acid and pepsin secretion, and enhances mucosal resistance to injury. It is an effective anti-ulcer agent and also has oxytocic properties.
See also: Diclofenac Sodium; Misoprostol (component of).

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Drug Indication
Misoprostol is indicated as a tablet to reduce the risk of NSAID induced gastric ulcers but not duodenal ulcers in high risk patients. Misoprostol is also formulated in combination with diclofenac to treat symptoms of osteoarthritis or rheumatoid arthritis in patients with a high risk of developing gastric ulcers. Misoprostol is used off label for the management of miscarriages, prevention of post partum hemorrhage, and is also used alone or in combination with mifepristone in other countries for first trimester abortions.
FDA Label
Induction of labour
Induction of labour

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Mechanism of Action
Misoprostol is a synthetic prostaglandin E1 analog that stimulates prostaglandin E1 receptors on parietal cells in the stomach to reduce gastric acid secretion. Mucus and bicarbonate secretion are also increased along with thickening of the mucosal bilayer so the mucosa can generate new cells. Misoprostol binds to smooth muscle cells in the uterine lining to increase the strength and frequency of contractions as well as degrade collagen and reduce cervical tone.
Misoprostol enhances natural gastromucosal defense mechanisms and healing in acid-related disorders, probably by increasing production of gastric mucus and mucosal secretion of bicarbonate.
Misoprostol inhibits basal and nocturnal gastric acid secretion by direct action on the parietal cells; also inhibits gastric acid secretion stimulated by food, histamine, and pentagastrin. It decreases pepsin secretion under basal, but not histamine stimulation. Misoprostol has no significant effect on fasting or postprandial gastrin or intrinsic factor output.

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Therapeutic Uses
Abortifacient Agents, Nonsteroidal; Anti-Ulcer Agents; Oxytocics
Misoprostol is indicated for the prevention of gastric ulcer associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, in patients at high risk of complications from gastric ulcer, such as the elderly, and in patients with concomitant disease or patients at high risk of developing gastric ulceration, such as those with a history of ulcer. /Included in US product labeling/
Misoprostol is indicated in the short-term treatment of duodenal ulcer. /NOT included in US product labeling/
The efficacy and tolerability of mifepristone in combo with misoprostol for termination of early pregnancy (up to 49 days of amenorrhea) are established.
For more Therapeutic Uses (Complete) data for MISOPROSTOL (8 total), please visit the HSDB record page.

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Drug Warnings
Misoprostol is contraindicated during pregnancy. Studies in humans have shown that misoprostol causes an increase in the frequency and intensity of uterine contractions. Misoprostol administration has also been associated with a higher incidence of uterine bleeding and expulsion of uterine contents. Miscarriages caused by misoprostol are likely to be incomplete, resulting in very serious medical complications, sometimes requiring hospitalization and surgery, and possibly causing infertility.
Patients of childbearing potential may use misoprostol if nonsteroidal anti-inflammatory drug (NSAID) therapy is required and patient is at high risk of complications from gastric ulcers associated with the use of NSAIDs, or is at high risk of developing gastric ulceration. Such patients must comply with effective contraceptive measures, must have had a negative serum pregnancy test within 2 weeks prior to initiation of therapy and must start misoprostol therapy only on the second or third day of the next normal menstrual period.
It is unlikely that misoprostol is distributed into breast milk since it is rapidly metabolized throughout the body. however, it is not known if the active metabolite, misoprostol acid, is distributed into breast milk. Therefore, administration of misoprostol to nursing women is not recommended because of the potential distribution of misoprostol acid, which could cause significant diarrhea in the nursing infant.
Misoprostol generally is well tolerated. The frequency of adverse effects does not appear to be affected by patient age in adults. The most frequent adverse effects associated with misoprostol therapy involve the GI tract (e.g., diarrhea, nausea, abdominal pain).
For more Drug Warnings (Complete) data for MISOPROSTOL (8 total), please visit the HSDB record page.

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Pharmacodynamics
Misoprostol is a prostaglandin E1 analog used to reduce the risk of NSAID induced gastric ulcers by reducing secretion of gastric acid from parietal cells. Misoprostol is also used to manage miscarriages and used alone or in combination with mifepristone for first trimester abortions. An oral dose of misoprostol has an 8 minute onset of action and a duration of action of approximately 2 hours, a sublingual dose has an 11 minute onset of action and a duration of action of approximately 3 hours, a vaginal dose has a 20 minute onset of action and a duration of action of approximately 4 hours, and a rectal dose has a 100 minute onset of action and a duration of action of approximately 4 hours.

C22H38O5

382.54

382.271

C, 69.07; H, 10.01; O, 20.91

59122-46-2

59122-46-2

5282381

Light yellow oil
Viscous liquid

1.1±0.1 g/cm3

497.3±45.0 °C at 760 mmHg

261-263°C

160.4±22.2 °C

0.0±2.9 mmHg at 25°C

1.525

2.91

2

5

14

27

487

3

O[C@H](C1)[C@@H]([C@H](C1=O)CCCCCCC(OC)=O)/C=C/CC(C)(O)CCCC

OJLOPKGSLYJEMD-URPKTTJQSA-N

InChI=1S/C22H38O5/c1-4-5-14-22(2,26)15-10-12-18-17(19(23)16-20(18)24)11-8-6-7-9-13-21(25)27-3/h10,12,17-18,20,24,26H,4-9,11,13-16H2,1-3H3/b12-10+/t17-,18-,20-,22?/m1/s1

methyl 7-[(1R,2R,3R)-3-hydroxy-2-[(E)-4-hydroxy-4-methyloct-1-enyl]-5-oxocyclopentyl]heptanoate

SC29333; SC 29333; Misoprostol; Cytotec; Misoprostolum; Isprelor; Misopess; SC-29333; SC-30249; SC 30249; SC30249

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: ~76 mg/mL (~198.7 mM)
Water: ~35 mg/mL
Ethanol: ~10 mg/mL

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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