Absorption, Distribution and Excretion
Betaine is rapidly absorbed and distributed. In healthy volunteers (n=12) given 50 mg/kg of betaine, the Cmax, tmax and AUC0,∞ were 0.939 mmol/L, 0.90 h and 5.52 mmol⋅h/L, respectively. No significant changes in absorption kinetics were observed after repeated betaine administration (100 mg/kg/day for 5 days). The absolute bioavailability of betaine anhydrous has not been determined.
Betaine is mainly eliminated by metabolism. With a slow elimination rate and assuming 100% bioavailability, the renal clearance of betaine is negligible (5% of total body clearance).
Based on a study done on healthy volunteers (n=12) given 50 mg/kg of betaine, the volume of distribution was 1.3 L/kg.
Based on a study done on healthy volunteers (n=12) given 50 mg/kg of betaine, total oral plasma drug clearance was 0.084 L/h⋅kg.
Betaine is absorbed from the small intestines into the enterocytes. It is released by the enterocytes into the portal circulation which carries it to the liver where there is significant first-pass extraction and first-pass metabolism of betaine. The principal metabolic reaction is the transfer of a methyl group from betaine to homocysteine via the enzyme betaine-homocysteine methyltransferase. The products of the reaction are L-methionine and dimethylglycine. Betaine hydrochloride is converted to betaine in the alkaline environment of the small intestine.
It is not known whether betaine is distributed into breast milk. However, its metabolic precursor, choline, is found in human breast milk in high concentrations .
... /The authors/ measured homocysteine, betaine, folate, vitamin B(6), and related compounds in serum/plasma from 500 healthy men and women aged 34 to 69 years before (fasting levels) and 6 hours after a standard methionine loading test. Choline, dimethylglycine, and folate were determinants of plasma betaine in a multiple regression model adjusting for age and sex. The increase in homocysteine after loading showed a strong inverse association with plasma betaine and a weaker inverse association with folate and vitamin B6. Fasting homocysteine showed a strong inverse relation to folate, a weak relation to plasma betaine, and no relation to vitamin B6. Notably, adjusted (for age and sex) dose-response curves for the postmethionine increase in homocysteine or fasting homocysteine versus betaine showed that the inverse associations were most pronounced at low serum folate, an observation that was confirmed by analyses of interaction ... Collectively, these results show that plasma betaine is a strong determinant of increase in homocysteine after methionine loading, particularly in subjects with low folate status. In 500 healthy subjects, postmethionine load increase in tHcy showed a stronger inverse relation to betaine than to folate and vitamin B6, whereas for fasting total homocysteine (tHcy) betaine was a weaker determinant than folate. For both tHcy modalities, the association with betaine was most pronounced in subjects with low folate status.
Thirty-four healthy men and women were supplied with doses of 1, 3 and 6 g betaine and then with 6 g betaine +1 mg folic acid for four consecutive 1-week periods. The mean plasma total homocysteine (tHcy) concentration decreased by 1.1 (NS), 10.0 and 14.0 % (P<0.001) after supplementation with 1, 3 and 6 g betaine respectively. A further decrease in plasma tHcy by 5 % (P<0.01) was achieved by combining 1 mg folic acid with the 6 g betaine dose. Plasma betaine increased from 31 (sd 13) to 255 (sd 136) umol/L in a dose-dependent manner (R(2) 0.97) ... /The authors/ conclude that plasma tHcy is lowered rapidly and significantly by 3 or 6 g betaine/d in healthy men and women.
... /The authors/ investigated the courses of plasma choline and betaine during normal human pregnancy and their relations to plasma total homocysteine (tHcy) ... Blood samples were obtained monthly; the initial samples were taken at gestational week (GW) 9, and the last samples were taken approximately 3 mo postpartum. The study population comprised 50 women of West African descent. Most of the subjects took folic acid irregularly ... Plasma choline (geometric x; 95% reference interval) increased continuously during pregnancy, from 6.6 (4.5, 9.7) umol/L at GW 9 to 10.8 (7.4, 15.6) umol/L at GW 36. Plasma betaine decreased in the first half of pregnancy, from 16.3 (8.6, 30.8) umol/L at GW 9 to 10.3 (6.6, 16.2) umol/L at GW 20 and remained constant thereafter ... /The authors/ confirmed a reduction in plasma tHcy, and the lowest concentration was found in the second trimester. From GW 16 onward, an inverse relation between plasma tHcy and betaine was observed. Multiple regression analysis showed that plasma betaine was a strong predictor of plasma tHcy from GW 20 onward ... The steady increase in choline throughout gestation may ensure choline availability for placental transfer with subsequent use by the growing fetus. Betaine becomes a strong predictor of tHcy during the course of pregnancy.

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Metabolism / Metabolites
Betaine is catabolized mainly in the mitochondria of liver and kidney cells. The transmethylation of betaine via betaine homocysteine methyl transferase (BHMT) leads to the formation of dimethylglycine.
Betaine is absorbed from the small intestines into the enterocytes. It is released by the enterocytes into the portal circulation which carries it to the liver where there is significant first-pass extraction and first-pass metabolism of betaine. The principal metabolic reaction is the transfer of a methyl group from betaine to homocysteine via the enzyme betaine-homocysteine methyltransferase. The products of the reaction are L-methionine and dimethylglycine. Betaine hydrochloride is converted to betaine in the alkaline environment of the small intestine.
/Betaine/ is a metabolite of choline ...

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Biological Half-Life
In healthy volunteers (n=12) given 50 mg/kg of betaine, the elimination half-life was 14.38 h. In volunteers given 100 mg/kg/day of betaine for 5 days, the distribution half-life was significantly longer, suggesting that the transport and redistribution processes of betaine were saturated.

Hepatotoxicity
In small, open label trials of betaine therapy for homocystinuria as well as in small controlled trials of betaine in other conditions (Alzheimer disease, nonalcoholic steatohepatitis), serum enzyme elevations and clinically apparent liver injury were not reported. Indeed, in some studies, betaine has been associated with significant declines in preexisting serum enzyme elevations in a proportion of patients with nonalcoholic fatty liver disease.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Interactions
The aim of this study was to assess the pharmacokinetics of orally administered betaine and its acute effect on plasma total homocysteine (tHcy) concentrations. Healthy volunteers (n = 10; 3 men, 7 women) with normal body weight (mean + or - SD, 69.5 + or - 17.0 kg), 40.8 + or - 12.4 yr old, participated in the study. The betaine doses were 1, 3, and 6 g. The doses were mixed with 150 mL of orange juice and ingested after a 12-hr overnight fast by each volunteer according to a randomized double-blind crossover design. Blood samples were drawn for 24 hr and a 24-hr urine collection was performed. Orally administered betaine had an immediate and dose-dependent effect on serum betaine concentration. Single doses of 3 and 6 g lowered plasma tHcy concentrations (P = 0.019 and P < 0.001, respectively), unlike the 1-g dose. After the highest dose, the concentrations remained low during the 24 hr of monitoring. The change in plasma tHcy concentration was linearly associated with betaine dose (P = 0.006) and serum betaine concentration (R2 = 0.17, P = 0.025). The absorption and elimination of betaine were dose dependent. The urinary excretion of betaine seemed to increase with an increasing betaine dose, although a very small proportion of ingested betaine was excreted via urine. In conclusion, a single dose of orally administered betaine had an acute and dose-dependent effect on serum betaine concentration and resulted in lowered plasma tHcy concentrations within 2 hr in healthy subjects.
The prophylactic efficiency of taurine or betaine pretreatment for the prevention of peroxidative changes induced by lipopolysaccharide treatment in the rat liver was investigated ... Lipopolysaccharide (10 mg/kg intraperitoneally) was given to rats pretreated with taurine (1.5%, w/v) or betaine (1.5%, w/v) in drinking water for 4 weeks and plasma transaminase activities as well as hepatic malondialdehyde, diene conjugate (DC), glutathione, alpha-tocopherol and ascorbic acid levels, and superoxide dismutase (SOD) and glutathione peroxidase activities were determined ... Significant increases in plasma transaminase activities and hepatic malondialdehyde and DC levels and decreases in hepatic glutathione and alpha-tocopherol levels and SOD and glutathione peroxidase activities were observed 6 h after lipopolysaccharide treatment. This treatment did not alter ascorbic acid levels in the liver compared with controls. Taurine or betaine pretreatment in lipopolysaccharide-injected rats caused significant decreases in plasma transaminase activities and hepatic malondialdehyde and DC levels, and significant increases in glutathione and alpha-tocopherol (not betaine) levels without changing ascorbic acid levels and SOD and glutathione peroxidase activities in the liver ... /According to the authors/ taurine or betaine pretreatment was effective in the prevention of lipopolysaccharide-induced hepatotoxicity and prooxidant status.
Concomitant use of betaine and folic acid may be additive with regard to the possible lowering of serum homocysteine levels.
... Remethylation of homocysteine to methionine can occur through either the folate-dependent methionine synthase pathway or the betaine-dependent betaine-homocysteine methyltransferase pathway. The relevance of betaine as a determinant of fasting total homocysteine (tHcy) is not known, nor is it known how the 2 remethylation pathways are interrelated ... The objectives of the study were to examine the relation between plasma betaine concentration and fasting plasma tHcy concentrations and to assess the effect of folic acid supplementation on betaine concentrations in healthy subjects ... A double-blind randomized trial of 6 incremental daily doses of folic acid (50-800 ug/day) or placebo was carried out in 308 Dutch men and postmenopausal women (aged 50 to 75 yr). Fasted blood concentrations of tHcy, betaine, choline, dimethylglycine, and folate were measured at baseline and after 12 wk of vitamin supplementation ... Concentrations of tHcy were inversely related to the betaine concentration (r = -0.17, P < 0.01), and the association was independent of age, sex, and serum concentrations of folate, creatinine, and cobalamin. Folic acid supplementation increased betaine concentration in a dose-dependent manner (P for trend = 0.018); the maximum increase (15%) was obtained at daily doses of 400 to 800 ug/day ... /The authors condluded/ the plasma betaine concentration is a significant determinant of fasting tHcy concentrations in healthy humans. Folic acid supplementation increases the betaine concentration, which indicates that the 2 remethylation pathways are interrelated.

[1]. Betaine Effects on Morphology, Proliferation, and p53-induced Apoptosis of HeLa Cervical Carcinoma Cells in Vitro. Asian Pac J Cancer Prev. 2015;16(8):3195-201.

[2]. Rectification of impaired adipose tissue methylation status and lipolytic response contributes to hepatoprotective effect of betaine in a mouse model of alcoholic liver disease. Br J Pharmacol. 2014 Sep;171(17):4073-86.

[3]. Reconsidering betaine as a natural anti-heat stress agent in poultry industry: a review. Trop Anim Health Prod. 2017 Oct;49(7):1329-1338.

Therapeutic Uses
... /The authors/ measured blood lipids in four placebo-controlled, randomised intervention studies that examined the effect of betaine (three studies, n = 151), folic acid (two studies, n = 75), and phosphatidylcholine (one study, n = 26) on plasma homocysteine concentrations ... /They/ combined blood lipid data from the individual studies and calculated a weighted mean change in blood lipid concentrations relative to placebo. Betaine supplementation (6 g/day) for 6 wk increased blood LDL cholesterol concentrations by 0.36 mmol/L (95% confidence interval: 0.25 to 0.46), and triacylglycerol concentrations by 0.14 mmol/L (0.04 to 0.23) relative to placebo. The ratio of total to HDL cholesterol increased by 0.23 (0.14 to 0.32). Concentrations of HDL cholesterol were not affected. Doses of betaine lower than 6 g/day also raised LDL cholesterol, but these changes were not statistically significant. Further, the effect of betaine on LDL cholesterol was already evident after 2 wk of intervention. Phosphatidylcholine supplementation (providing approximately 2.6 g/day of choline) for 2 wk increased triacylglycerol concentrations by 0.14 mmol/L (0.06 to 0.21), but did not affect cholesterol concentrations. Folic acid supplementation (0.8 mg/day) had no effect on lipid concentrations.
Anhydrous betaine has been useful in the treatment of homocystinuria and betaine may be helpful in other conditions characterized by elevated plasma homocysteine levels. Betaine hydrochloride is used as a digestive aid in some. There is some suggestion in animal research that betaine may be hepatoprotective in some circumstances.
Cystadane (betaine anhydrous for oral solution) is indicated for the treatment of homocystinuria to decrease elevated homocysteine blood levels. Included within the category of homocystinuria are deficiencies or defects in: cystathionine beta-synthase (CBS), 5,10-methylenetetrahydrofolate reductase (MTHFR), and cobalamin cofactor metabolism (cbl).
VET: Betaine glucuronate is, together with 2-aminoethanol glucuronate, used as active principle in a product for symptomatic treatment of acute or chronic disorders of the liver, such as endogenous metabolic disorders, cases of exogenous intoxication or disorders related to parasite infestations. It is administered by injection in cattle, horses, sheep, goats and pigs ... . /Betaine glucuronate/
For more Therapeutic Uses (Complete) data for BETAINE (14 total), please visit the HSDB record page.

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Drug Warnings
It is not known whether betaine is excreted in human milk (although its metabolic precursor, choline, occurs at high levels in human milk). Because many drugs are excreted in human milk, caution should be exercised when Cystadane is administered to a nursing woman.
Therapy with Cystadane should be directed by physicians knowledgeable in the management of patients with homocystinuria.
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
Patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency may also have elevated plasma methionine concentrations. Treatment with Cystadane may further increase methionine concentrations due to the remethylation of homocysteine to methionine. Cerebral edema has been reported in patients with hypermethioninemia, including a few patients treated with Cystadane. Plasma methionine concentrations should be monitored in patients with CBS deficiency. Plasma methionine concentrations should be kept below 1,000 umol/L through dietary modification and, if necessary, a reduction of Cystadane dose.
For more Drug Warnings (Complete) data for BETAINE (11 total), please visit the HSDB record page.

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Pharmacodynamics
Betaine decreases plasma homocysteine concentrations in homocystinuria cases caused by deficiencies or defects in cystathionine beta-synthase (CBS), 5,10-methylenetetrahydrofolate reductase (MTHFR), and cobalamin cofactor metabolism (cbl). The decrease of homocysteine is estimated to be 20-30% of pre-treatment levels. Betaine supplementation in patients with homocystinuria also improves metabolic abnormalities in cerebrospinal fluid. Reports have shown that depending on the type of homocystinuria, the therapeutic effectiveness of betaine alone may be limited, insufficient to decrease total homocysteine levels and prevent clinical symptoms. In patients with homocystinuria due to cystathionine beta-synthase (CBS) deficiency, betaine should be used when serum total homocysteine levels remain high despite dietary therapy. Patients taking betaine for several years do not show evidence of tolerance. Also, betaine concentrations are not correlated with homocysteine concentrations. In patients with MTHFR deficiency and cbl defects, betaine may increase methionine and S-adenosyl methionine (SAM) plasma levels. Patients with CBS deficiency without a dietary restriction of methionine may accumulate excessive amounts of methionine. Clinical data shows that in patients with CBS deficiency, increased plasma methionine levels were associated with cerebral edema.

C5H11NO2

117.15

117.078

107-43-7

590-46-5 (hydrochloride)

247

White to off-white solid powder

1.00 g/mL at 20 °C

301-305 °C (dec.)

-3.25

0

2

1

8

87.6

0

[O-]C(C([H])([H])[N+](C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])=O

KWIUHFFTVRNATP-UHFFFAOYSA-N

InChI=1S/C5H11NO2/c1-6(2,3)4-5(7)8/h4H2,1-3H3

2-(trimethylazaniumyl)acetate

Abromine LycineBetaine

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

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.)