为了阻止染色体断裂和DNA低甲基化，叶酸钠是必不可少的[1]。

在具有这种行为的小鼠模型中，叶酸钠（10、50 或 100 mg/kg；口服）表现出类似抗抑郁的作用 [2]。适应新环境的小鼠不会表现出叶酸钠（1、10 nmol/位点）的任何精神兴奋作用[2]。在幼鼠中，口服叶酸钠（1、5 mg/kg）可抑制肝基因表达的表观遗传变化 [3]。

Animal/Disease Models: 30-40 g Swiss mice [2]
Doses: 10, 50, 100 mg/kg
Route of Administration: Oral
Experimental Results: diminished immobility time in forced swim test (FST) (F324=11.21), produced significant Immobility time in tail suspension test (TST) (F3,20=5.71).

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Animal/Disease Models: 30-40 g Swiss mice [2]
Doses: 1-10 nmol/site
Route of Administration: Intracerebroventricular injection
Experimental Results: diminished mouse FST (F3,22=12.31) and TST (F3,22=5.50) immobile time).

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Animal/Disease Models: Virgin female Wistar rats [3]
Doses: 1, 5 mg/kg (180 g/kg protein plus 1 mg/kg folic acid or 90 g/kg casein plus 1, 5 mg/kg folic acid)
Route of Administration: Oral administration
Experimental Results: Prevention of epigenetic modifications in liver gene expression in offspring.

Absorption, Distribution and Excretion
Folic acid is absorbed rapidly from the small intestine, primarily from the proximal portion. Naturally occurring conjugated folates are reduced enzymatically to folic acid in the gastrointestinal tract prior to absorption. Folic acid appears in the plasma approximately 15 to 30 minutes after an oral dose; peak levels are generally reached within 1 hour.
After a single oral dose of 100 mcg of folic acid in a limited number of normal adults, only a trace amount of the drug appeared in the urine. An oral dose of 5 mg in 1 study and a dose of 40 mcg/kg of body weight in another study resulted in approximately 50% of the dose appearing in the urine. After a single oral dose of 15 mg, up to 90% of the dose was recovered in the urine. A majority of the metabolic products appeared in the urine after 6 hours; excretion was generally complete within 24 hours. Small amounts of orally administered folic acid have also been recovered in the feces. Folic acid is also excreted in the milk of lactating mothers.
Tetrahydrofolic acid derivatives are distributed to all body tissues but are stored primarily in the liver.
Folic acid is absorbed rapidly from the GI tract following oral administration oral administration; the vitamin is absorbed mainly in the proximal portion of the small intestine.
The monoglutamate forms of folate, including folic acid, are transported across the proximal small intestine via a saturable pH-dependent process. Higher doses of the pteroylmonoglutamates, including folic acid, are absorbed via a nonsaturable passive diffusion process. The efficiency of absorption of the pteroylmonoglutamates is greater than that of pteroylpolyglutamates.
Following oral administration, peak folate activity in blood occurs within 30 to 60 minutes. Synthetic folate is almost 100% bioavailable when administered in fasting individuals. While the bioavailability of naturally occurring folate in food is about 50%, bioavailability of synthetic folic acid consumed with a meal ranges from 85 to 100%.
Approximately two-thirds of folate in plasma is protein bound. ... When pharmacologic doses of folic acid are administered, a significant amount of unchanged folic acid is found in the plasma. The liver contains more than 50% of the body stores of folate, or about 6 to 14 milligrams. The total body store of folate is about 12 to 28 miligrams.
For more Absorption, Distribution and Excretion (Complete) data for FOLIC ACID (11 total), please visit the HSDB record page.

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Metabolism / Metabolites
Folic acid is metabolized in the liver into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF) by the enzyme dihydrofolate reductase (DHFR).
Folic acid is converted (in the presence of ascorbic acid) in the liver and plasma to its metabolically active form (tetrahydrofolic acid) by dihydrofolate reductase.
Following absorption of 1 mg or less, folic acid is largely reduced and methylated in the liver to N-methyltetrahydrofolic acid... .
The folates are taken up by the liver and metabolized to polyglutamate derivatives (principally pteroylpentaglutamate), via the action of folypolyglutamate synthase. ... Folate polyglutamates are released from the liver to the systemic circulation and to the bile. When released from the liver into the circulation, the polyglutamate forms are hydrolyzed by gamma-glutamylhydrolase and reconverted to the monoglutamate forms.

Toxicity Summary
IDENTIFICATION: Folic acid is an antianaemic vitamin. Origin of the substance: Folic acid was isolated from green leafy vegetables, liver, yeast and fruits. Synthetic folic acid is commercially available. Yellow to orange brown crystalline powder which is odorless. Readily soluble in alkali, hydroxides and carbonates. Insoluble in alcohol, acetone, chloroform and ether. Solutions are inactivated by ultraviolet light. Alkaline solutions are sensitive to oxidation and acid solutions are sensitive to heat. Indications: For the prevention and treatment of vitamin B deficiency. For the treatment of megaloblastic anemia and macrocytic anemia due to folic acid deficiency. Folic acid supplements may be required in low birth weight infants, infants breastfed by folic acid deficient mothers, or those with prolonged diarrhea and infection. Other conditions which may increase folic acid requirements include alcoholism, hepatic disease, hemolytic anemia, lactation, oral contraceptive use and pregnancy. It has been given to pregnant mothers to reduce the risk of birth defects. HUMAN EXPOSURE: Main risks and target organs: Folic acid is relatively non-toxic. However, there have been reports of reactions to parenteral injections. Allergic reactions to folic acid have been rarely reported. Summary of clinical effects: Severe allergic reactions are characterized by hypotension, shock, bronchospasm, nausea, vomiting, rash, erythema. Itching may also occur. Adverse gastrointestinal and central nervous system effects have been reported. Treatment with folic acid is usually well tolerated except for rare reports of allergic reactions. Bioavailability: Folic acid is rapidly absorbed from gastrointestinal tract following oral administration. Peak folate activity in blood is 30 to 60 minutes after oral administration. Contraindications: It should be given with caution to patients with abnormal renal function. It is also contra-indicated in patients who show hypersensitivity reactions to folic acid. Caution is advised in patients who may have folate dependent tumours. Folic acid should never be given alone or in conjunction with inadequate amounts of Vitamin B12 for the treatment of undiagnosed megaloblastic anaemia. Although folic acid may produce a haematopoietic response in patients with megaloblastic anaemia due to Vitamin B12, it fails to prevent the onset of subacute combined degeneration of the cord. Absorption by route of exposure: Oral: Folic acid is rapidly absorbed from the proximal part of the gastrointestinal tract following oral administration. It is mainly absorbed in the proximal portion of the small intestine. The naturally occurring folate polyglutamate is enzymatically hydrolyzed to monoglutamate forms in the gastrointestinal tract prior to absorption. The peak folate activity in blood after oral administration is within 30 to 60 minutes. Enterohepatic circulation of folate has been demonstrated. Distribution by route of exposure: Tetrahydrofolic acid and its derivatives are distributed in all body tissues. The liver contains half of the total body stores of folate and is the principal storage site. Metabolism: Folic acid once absorbed is acted upon by hepatic dihydrofolate reductase to convert to its metabolically active form which is tetrahydrofolic acid. Following absorption, folic acid is largely reduced and methylated in the liver to N-5 methyltetrahydrofolic acid, which is the main transporting and storage form of folate in the body. Larger doses may escape metabolism by the liver and appear in the blood mainly as folic acid. Elimination by route of exposure: Oral: Following oral administration of single doses of folic acid in health adults, only a trace amount of the drug appears in urine. Following administration of large doses, the renal tubular reabsorption maximum is exceeded and excess folate is excreted unchanged in urine. Small amounts of orally administered folic acid have been recovered from feces. Pharmacodynamics: Folic acid is transformed into different coenzymes that are responsible for various reactions of intracellular metabolism mainly conversion of homocysteine to methionine, conversion of serine to glycine, synthesis of thymidylate, histidine metabolism, synthesis of purines and utilization or generation of formate. In man, nucleoprotein synthesis and the maintenance of normal erythropoiesis requires exogenous folate. Folic acid is the precursor of tetrahydrofolic acid which is active and acts as a co-factor for 1-carbon transfer reactions in the biosynthesis of purines and thymidylates of nucleic acids. Adults: There is little data available on folic acid toxicity in humans. A case of two patients who showed exacerbation of psychotic behavior during treatment with folic acid has been reported. Cytomorphological effects of folic acid were studied using in-vitro establishment human oral epithelium. A concentration twice that used clinically did not induce marked cytotoxic reaction in cultured cells. The most pronounced changes were cultures which showed degenerating cells showing edema, increased translucency of the cytoplasm, flattened cells and atypical filaments. Interactions: Folic acid therapy may increase phenytoin metabolism in folate deficient patients resulting in decreased phenytoin serum concentration. It has also been reported that concurrent administration of folic acid and chloramphenicol in folate deficient patients may result in antagonism of the hematopoietic response to folic acid. The use of ethotoin or mephenytoin concurrently with folic acid may decrease the effects of hydantoins by increasing hydantoin metabolism. Trimethoprim acts as a folate antagonist by inhibiting dihydrofolate reductase, so in patients receiving this drug leucovorin calcium must be given instead of folic acid. Folic acid may also interfere with the effects of pyrimethamine. Aminopterin (4 aminofolic acid) and methotrexate (4 amino- 10 methylfolic acid) antagonizes reduction of folic acid to tetrahydrofolic acid. Methotrexate continues to be used as an antineoplastic drug whose activity may be dependent on blocking certain syntheses, of purines, in which folic acid is required, thereby depriving neoplastic cells of compounds essential for their proliferation. Calcium leucovorin is used therapeutically as a potent antidote for the toxic effects of folic acid antagonists used as antineoplastic agents. Methotrexate or pyrimethamine or triamterene also acts as folate antagonist by inhibiting dihydrofolic reductase. Analgesics, anticonvulsants, antimalarials and corticosteroids may cause folic acid deficiency. Main adverse effects: Allergic reactions to folic acid have been rarely reported including erythema, rash, itching, general malaise and bronchospasm. Adverse gastrointestinal and central nervous system effects have been reported in patients receiving 15 mg of folic acid daily for one month. ANIMAL/PLANT STUDIES: Mode of action: Folic acid is relatively non-toxic. Toxicity studies in mice showed that folic acid could cause convulsions, ataxia and weakness. Histopathological studies in some strains of mice showed that toxic doses may also cause acute renal tubular necrosis. A possible relationship between folic acid neurotoxicity and cholinergic receptors in the pyriform cortex and amygdala has been shown.

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Interactions
The use of high dose folic acid concomitantly with pyrimethamine to prevent bone marrow depression may cause a pharmacodynamic antagonism of the antiparasitic effect of pyrimethamine.
Nonsteroidal antiinflammatory drugs (NSAIDS), including ibuprofen, indomethacin, naproxen, mefenamic acid, piroxicam, and sulindac taken at high therapeutic dosages may exert antifolate activity.
Folic acid supplementation in mice was found to augment the therapeutic activity and ameliorate the adverse reactions of the ... antifolate cancer chemotherapeutic agent lometrexol.
The /daily/ use of folic acid ... was found to enhance the antidepressant action of fluoxetine ...
For more Interactions (Complete) data for FOLIC ACID (17 total), please visit the HSDB record page.

[1]. Folic acid safety and toxicity: a brief review. Am J Clin Nutr. 1989 Aug;50(2):353-8.

[2]. Folic acid administration produces an antidepressant-like effect in mice: evidence for the involvement of the serotonergic and noradrenergic systems. Neuropharmacology. 2008 Feb;54(2):464-73.

[3]. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005 Jun;135(6):1382-6.

[4]. Folic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet. 2010 Aug;49(8):535-48.

Therapeutic Uses
Hematinics
Folic acid is indicated for prevention and treatment of folic acid deficiency states , including megaloblastic anemia and anemias of nutritional origin, pregnancy, infancy, or childhood.
Recommended intakes may be increased and /or supplementation may be necessary in the following persons or conditions (based on documented folic acid deficiency): Alcoholism, hemolytic anemia, chronic fever, gastrectomy, chronic hemodialysis, infants (low birth weight, breast-fed, or those receiving unfortified formulas such as evaporated milk or goats milk), Intestinal disease (celiac disease, tropical sprue, persistent diarrhea), malabsorption syndromes associated with hepatic-biliary disease (hepatic function impairment, alcoholism with cirrhosis), /and/ prolonged stress.
MEDICATION (VET): ... To prevent macrocytic anemia, embryonic death, cervical paralysis, and perosis In chicks.
For more Therapeutic Uses (Complete) data for FOLIC ACID (7 total), please visit the HSDB record page.

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Drug Warnings
Allergic reactions to folic acid preparations have been reported rarely and have included erythema, rash, itching, general malaise, and bronchospastic respiratory difficulty.
Adverse GI effects such as anorexia, nausea, abdominal distention, flatulence, and a bitter/bad taste and adverse CNS effects such as altered sleep patterns, difficulties concentrating, irritability, overactivity, excitement, mental depression, confusion, and impaired judgement have been reported rarely in patients receiving 15 mg of folic acid daily for one month.
Decreased serum vitamin B12 concentration may occur in patients receiving prolonged folic acid therapy.
Folic acid should be administered with extreme caution in patients with undiagnosed anemia, since folic acid may obscure the diagnosis of pernicious anemia by alleviating hematologic manifestations of the disease while allowing the neurologic complications to progress. This may result in severe nervous system damage before the correct diagnosis is made.
For more Drug Warnings (Complete) data for FOLIC ACID (7 total), please visit the HSDB record page.

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Pharmacodynamics
Folic acid is a water-soluble B-complex vitamin found in foods such as liver, kidney, yeast, and leafy, green vegetables. Also known as folate or Vitamin B9, folic acid is an essential cofactor for enzymes involved in DNA and RNA synthesis. More specifically, folic acid is required by the body for the synthesis of purines, pyrimidines, and methionine before incorporation into DNA or protein. Folic acid is the precursor of tetrahydrofolic acid, which is involved as a cofactor for transformylation reactions in the biosynthesis of purines and thymidylates of nucleic acids. Impairment of thymidylate synthesis in patients with folic acid deficiency is thought to account for the defective deoxyribonucleic acid (DNA) synthesis that leads to megaloblast formation and megaloblastic and macrocytic anemias. Folic acid is particularly important during phases of rapid cell division, such as infancy, pregnancy, and erythropoiesis, and plays a protective factor in the development of cancer. As humans are unable to synthesize folic acid endogenously, diet and supplementation is necessary to prevent deficiencies. In order to function properly within the body, folic acid must first be reduced by the enzyme dihydrofolate reductase (DHFR) into the cofactors dihydrofolate (DHF) and tetrahydrofolate (THF). This important pathway, which is required for de novo synthesis of nucleic acids and amino acids, is disrupted by anti-metabolite therapies such as [DB00563] as they function as DHFR inhibitors to prevent DNA synthesis in rapidly dividing cells, and therefore prevent the formation of DHF and THF. In general, folate serum levels below 5 ng/mL indicate folate deficiency, and levels below 2 ng/mL usually result in megaloblastic anemia.

C19H17N7O6-2.2[NA+]

485.36118

463.122

6484-89-5

Folic acid;59-30-3

135398658

Yellowish-orange crystals; extremely thin platelets (elongated @ 2 ends) from hot water

482 °F (decomposes) (NTP, 1992)
250 °C

-1.1

216.11

6

10

9

32

767

1

C1=CC(=CC=C1C(=O)NC(CCC(=O)[O-])C(=O)[O-])NCC2=CN=C3C(=N2)C(=O)NC(=N3)N.[Na+].[Na+]

OVBPIULPVIDEAO-LBPRGKRZSA-N

InChI=1S/C19H19N7O6/c20-19-25-15-14(17(30)26-19)23-11(8-22-15)7-21-10-3-1-9(2-4-10)16(29)24-12(18(31)32)5-6-13(27)28/h1-4,8,12,21H,5-7H2,(H,24,29)(H,27,28)(H,31,32)(H3,20,22,25,26,30)/t12-/m0/s1

(2S)-2-[[4-[(2-amino-4-oxo-3H-pteridin-6-yl)methylamino]benzoyl]amino]pentanedioic 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)

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。