Singapore Drugs Database

Indication

For treatment of pernicious anemia (due to lack of or inhibition of intrinsic factor) and for prevention and treatment of vitamin B 12 deficiency [L2064], [L2068]. Values below approximately 170–250 pg/mL (120–180 picomol/L) for adults suggest a vitamin B12 deficiency. Despite this, evidence suggests that serum vitamin B12 concentrations may not accurately reflect intracellular concentrations of the vitamin [L2064]. It is therefore difficult to diagnose vitamin B12 deficiency.

Mechanism of Action

Vitamin B12 is used in the body in two forms: Methylcobalamin and 5-deoxyadenosyl cobalamin. The enzyme methionine synthase needs methylcobalamin as a cofactor. This enzyme is involved in the conversion of the amino acid homocysteine into methionine. Methionine, is required for DNA methylation [L2064], [L2068]. Vitamin B12 is converted to coenzyme B12 in tissues. This form is required for the conversion of methylmalonate to succinate and the synthesis of methionine from homocysteine (a reaction also requiring folate) [L2068]. Without coenzyme B12, tetrahydrofolate cannot be regenerated from its inactive storage form, _5-methyl tetrahydrofolate_, leading to functional folate deficiency. Vitamin B12 also may be involved in maintaining sulfhydryl (SH) groups in the reduced form needed by many SH-activated enzyme systems [L2068]. Via the above reactions, vitamin B12 is associated with both fat and carbohydrate metabolism, as well as protein synthesis [L2068]. _5-Deoxyadenosyl_ cobalamin is a cofactor needed by the enzyme that acts to convert _L-methylmalonyl-CoA_ to _succinyl-CoA_. This conversion is an important step in the extraction of energy from proteins and fats. Additionally, _succinyl CoA_ is necessary for the production of hemoglobin, the substance that carries oxygen in red blood cells [L2064]. _L-methylmalonyl-CoA mutase_ converts L-methylmalonyl-CoA to succinyl-CoA in the degradation of propionate, an important biochemical reaction in the metabolism of lipids and proteins. _Succinyl-CoA_ is also required for hemoglobin synthesis [L2064].

Pharmacokinetics

Absorption

Approximately 56% of a 1 mcg oral dose of vitamin B12 is absorbed, however, absorption decreases significantly when intrinsic factor capacity is exceeded (at 1–2 mcg of vitamin B12) [L2064]. Readily absorbed in the lower half of the ileum [L2067]. Bioavailability of the nasal gel vitamin B12 and spray forms compared to intramuscular injection are about 9% and 6%, respectively [L2068]. Because the intranasal forms have lower absorption than the IM dosage form, intranasal B12 forms dosed administered once weekly. After 1 month of treatment in pernicious anemia, the weekly dosing of 500 mcg B12 intranasal gel resulted in a significant increase in B12 levels in comparison to a once-monthly 100 mcg IM dose [L2068].

Distribution

Once absorbed, vitamin B12 is highly bound to transcobalamin II, a specific B-globulin carrier protein and is distributed and stored primarily in the liver as coenzyme B12 [L2068]. It has been found that the distribution of vitamin B12 is dependent on the current cobalamine status, from animal studies [L2067]. The bone marrow also stores a high amount of absorbed vitamin B12 [L2068]. This vitamin crosses the placenta and is found distributed in breast milk. Enterohepatic recirculation conserves systemic stores of Vitamin B12 [L2067].

Metabolism

Mainly Hepatic [A32397], [L2058]. Vitamin B12 serves as a cofactor for methionine synthase and _L-methylmalonyl-CoA mutase_ enyme. Methionine synthase catalyzes the conversion of homocysteine to methionine during metabolism. Methionine is necessary for the formation of S-adenosylmethionine, a universal methyl donor for about 100 substrates, including DNA, RNA, hormones, proteins, and lipids [L2064]. Vitamin B12, which is bound to protein in food, is released following the activity of hydrochloric acid and gastric protease in the stomach. When synthetic vitamin B12 is added to fortified foods and dietary supplements, it is found in the free form and, and does not require this separation step. Free vitamin B12 then binds with intrinsic factor (IF), a glycoprotein secreted by the parietal cells of the stomach, and the newly formed complex undergoes absorption within the distal ileum by receptor-mediated endocytosis [L2071]. Intestinal microorganisms produce cobalamin in the colon, however, not absorbed and thus vitamin B12 must be supplied with the food. In mammals, the assimilation and transport of dietary cobalamin is performed by three successive proteins, haptocorrin (HC), gastric intrinsic factor (IF) and transcoba- lamin. Cobalamin is required by cells for two enzyme cofactors, _methyl-Cbl_ for _methionine synthase_ and _50 -deoxyadenosyl-Cbl (Ado-Cbl)_ for _methyl- malonyl-CoA mutase_ [L2068]. In the stomach, Cobalamin is firstly bound to salivary HC. Following proteolytic cleavage of HC into 2-3 fragments in the duodenum, and is then transferred to IF. Mucosal cells in the terminal ileum absorb the IF-Cobalamin complex by a process called _endocytosis_ by the _cubilin_-amnionless receptor [L2068]. In the enterocyte (intestinal cell), Cobalamin is freed from IF and appears in the blood combined with transcobalamin which carries cobalamin to cells. Only the fraction of Cbl bound to TC is quickly taken up by endocytosis by a specific receptor of yet unknown structure, present on most cell types [L2068]. The other Cbl- transporting protein in plasma is homocysteine. Its ability to promote cellular uptake of cobalamin is found to be limited, but it is thought to serve as a storage protein as well as scavenger of inactive Cbl- analogues [L2071].

Elimination

Toxicity

Anaphylactic reactions (skin rash, itching, wheezing) post parenteral administration has occurred. The Institute of Medicine (IOM), USA, did not establish an upper limit for vitamin B12 because of its low potential for toxicity. In Dietary Reference Intakes [L2066]: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline, the IOM declares that “no adverse effects have an association with excess vitamin B12 intake from both food and dietary supplements in healthy individuals” [L2066]. Findings from intervention trials support these conclusions. In the NORVIT and HOPE 2 trials, vitamin B12 supplementation (in combination with folic acid and vitamin B6) did not cause any serious adverse events when administered at doses of 0.4 mg for 40 months (NORVIT trial) and 1.0 mg for 5 years (HOPE 2 trial) [A32388, A32389]. Parenteral methylcobalamin is classified as pregnancy category C. Adequate studies in humans have not been conducted; however, no maternal or fetal complications have been associated with doses that are recommended during pregnancy, and appropriate treatment should not be withheld from pregnant women with vitamin B12 responsive anemias. Conversely, pernicious anemia resulting from vitamin B12 deficiency may cause infertility or poor pregnancy outcomes. Vitamin B12 deficiency has occurred in breast-fed infants of vegetarian mothers whose diets contain no animal products (e.g., eggs, dairy), even though the mothers had no symptoms of deficiency at the time. Maternal requirements for vitamin B12 increase during pregnancy [L2064].

Active Ingredient/Synonyms

Cyanocob(III)alamin | Vitamin B12 | Vitamin B12 complex | Vitamin B12 NOS | Cyanocobalamin |

Indication

For improvement in appearance of moderate to severe fullness associated with submental fat in adults.

Mechanism of Action

As a bile acid, deoxycholic acid emulsifies fat in the gut. Synthetically derived deoxycholic acid, when injected, stimulates a targeted breakdown of adipose cells by disrupting the cell membrane and causing adipocytolysis. This results in an inflammatory reaction and clearing of the adipose tissue remnants by macrophages. Deoxycholic acid's actions are reduced by albumin and tissue-associated proteins, therefore its effect is limited to protein-poor subcutaneous fat tissue. Protein-rich tissues like muscle and skin are unaffected by deoxycholic acid, contributing to its safety profile.

Pharmacokinetics

Absorption

Deoxycholic acid is rapidly absorbed after subcutaneous administration. After maximum recommended single treatment dose, 100mg, the post-treatment plasma levels returned to endogenous levels within 24 hours. With the proposed treatment guideline, no accumulation is expected.

Distribution

Metabolism

Deoxycholic acid is not metabolized to any significant extent under normal conditions.

Elimination

Active Ingredient/Synonyms

(3α,5β,12α)-3,12-dihydroxycholan-24-oic acid | 3alpha,12alpha-Dihydroxy-5beta-cholanic acid | 7α-deoxycholic acid | deoxycholate | desoxycholic acid | Desoxycholsäure | Deoxycholic Acid |

Indication

Pyridoxine is indicated for the treatment of vitamin B6 deficiency and for the prophylaxis of [DB00951]-induced peripheral neuropathy. It is also approved by Health Canada for the treatment of nausea and vomiting in pregnancy in a combination product with [DB00366] (as the commercially available product Diclectin).

Mechanism of Action

Vitamin B6 is the collective term for a group of three related compounds, pyridoxine (PN), pyridoxal (PL) and pyridoxamine (PM), and their phosphorylated derivatives, pyridoxine 5'-phosphate (PNP), pyridoxal 5'-phosphate (PLP) and pyridoxamine 5'-phosphate (PMP). Although all six of these compounds should technically be referred to as vitamin B6, the term vitamin B6 is commonly used interchangeably with just one of them, pyridoxine. Vitamin B6, principally in its biologically active coenzyme form pyridoxal 5'-phosphate, is involved in a wide range of biochemical reactions, including the metabolism of amino acids and glycogen, the synthesis of nucleic acids, hemogloblin, sphingomyelin and other sphingolipids, and the synthesis of the neurotransmitters serotonin, dopamine, norepinephrine and gamma-aminobutyric acid (GABA).

Pharmacokinetics

Absorption

The B vitamins are readily absorbed from the gastrointestinal tract, except in malabsorption syndromes. Pyridoxine is absorbed mainly in the jejunum. The Cmax of pyridoxine is achieved within 5.5 hours.

Distribution

Pyridoxine main active metabolite, pyridoxal 5’-phosphate, is released into the circulation (accounting for at least 60% of circulating vitamin B6) and is highly protein bound, primarily to albumin.

Metabolism

Pyridoxine is a prodrug primarily metabolized in the liver. The metabolic scheme for pyridoxine is complex, with formation of primary and secondary metabolites along with interconversion back to pyridoxine. Pyridoxine's major metabolite is 4-pyridoxic acid.

Elimination

Toxicity

Oral Rat LD50 = 4 gm/kg. Toxic effects include convulsions, dyspnea, hypermotility, diarrhea, ataxia and muscle weakness.

Active Ingredient/Synonyms

2-Methyl-3-hydroxy-4,5-dihydroxymethylpyridine | 3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridine | 3-Hydroxy-4,5-dimethylol-alpha-picoline | 5-Hydroxy-6-methyl-3,4-pyridinedimethanol | Pyridoxine | Pyridoxol | Vitamin B6 | Pyridoxine |

Indication

For the treatment of ariboflavinosis (vitamin B2 deficiency).

Mechanism of Action

Binds to riboflavin hydrogenase, riboflavin kinase, and riboflavin synthase. Riboflavin is the precursor of flavin mononucleotide (FMN, riboflavin monophosphate) and flavin adenine dinucleotide (FAD). The antioxidant activity of riboflavin is principally derived from its role as a precursor of FAD and the role of this cofactor in the production of the antioxidant reduced glutathione. Reduced glutathione is the cofactor of the selenium-containing glutathione peroxidases among other things. The glutathione peroxidases are major antioxidant enzymes. Reduced glutathione is generated by the FAD-containing enzyme glutathione reductase.

Pharmacokinetics

Absorption

Vitamin B2 is readily absorbed from the upper gastrointestinal tract.

Distribution

Metabolism

Hepatic.

Elimination

Active Ingredient/Synonyms

1-Deoxy-1-(7,8-dimethyl-2,4-dioxo-3,4-dihydrobenzo[g]pteridin-10(2H)-yl)pentitol | 6,7-Dimethyl-9-D-ribitylisoalloxazine | 7,8-Dimethyl-10-(D-ribo-2,3,4,5-tetrahydroxypentyl)isoalloxazine | 7,8-Dimethyl-10-ribitylisoalloxazine | Lactoflavin | Lactoflavine | Riboflavina | Riboflavine | Riboflavinum | Vitamin B2 | Vitamin Bi | Vitamin G | Riboflavin |

Indication

For the treatment of thiamine and niacin deficiency states, Korsakov's alcoholic psychosis, Wernicke-Korsakov syndrome, delirium, and peripheral neuritis.

Mechanism of Action

It is thought that the mechanism of action of thiamine on endothelial cells is related to a reduction in intracellular protein glycation by redirecting the glycolytic flux. Thiamine is mainly the transport form of the vitamin, while the active forms are phosphorylated thiamine derivatives. There are five known natural thiamine phosphate derivatives: thiamine monophosphate (ThMP), thiamine diphosphate (ThDP), also sometimes called thiamine pyrophosphate (TPP), thiamine triphosphate (ThTP), and the recently discovered adenosine thiamine triphosphate (AThTP), and adenosine thiamine diphosphate. Each derivative has unique functions, however, most are involved as coenzymes.

Pharmacokinetics

Absorption

Absorbed mainly from duodenum, by both active and passive processes

Distribution

Metabolism

Hepatic

Elimination

Toxicity

Thiamine toxicity is uncommon; as excesses are readily excreted, although long-term supplementation of amounts larger than 3 gram have been known to cause toxicity. Oral mouse LD₅₀ = 8224 mg/kg, oral rat LD₅₀ = 3710 mg/kg.

Active Ingredient/Synonyms

Aneurin | Antiberiberi factor | Thiamin | thiamine | thiamine(1+) | thiamine(1+) ion | thiaminium | tiamina | Vitamin B1 | Thiamine |