Singapore Drugs Database

Indication

For the treatment of vitamin D deficiency or insufficiency, refractory rickets (vitamin D resistant rickets), familial hypophosphatemia and hypoparathyroidism, and in the management of hypocalcemia and renal osteodystrophy in patients with chronic renal failure undergoing dialysis. Also used in conjunction with calcium in the management and prevention of primary or corticosteroid-induced osteoporosis.

Mechanism of Action

The first step involved in the activation of vitamin D3 is a 25-hydroxylation which is catalysed by the 25-hydroxylase in the liver and then by other enzymes. The mitochondrial sterol 27-hydroxylase catalyses the first reaction in the oxidation of the side chain of sterol intermediates. The active form of vitamin D3 (calcitriol) binds to intracellular receptors that then function as transcription factors to modulate gene expression. Like the receptors for other steroid hormones and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA. In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription. Calcitriol increases the serum calcium concentrations by: increasing GI absorption of phosphorus and calcium, increasing osteoclastic resorption, and increasing distal renal tubular reabsorption of calcium. Calcitriol appears to promote intestinal absorption of calcium through binding to the vitamin D receptor in the mucosal cytoplasm of the intestine. Subsequently, calcium is absorbed through formation of a calcium-binding protein.

Pharmacokinetics

Absorption

Readily absorbed

Distribution

Metabolism

Within the liver, cholecalciferal is hydroxylated to calcidiol (25-hydroxycholecalciferol) by the enzyme 25-hydroxylase. Within the kidney, calcidiol serves as a substrate for 1-alpha-hydroxylase, yielding calcitriol (1,25-dihydroxycholecalciferol), the biologically active form of vitamin D3.

Elimination

Toxicity

Hypercalcemia - Early symptoms of hypercalcemia, include nausea and vomiting, weakness, headache, somnolence, dry mouth, constipation, metallic taste, muscle pain and bone pain. Late symptoms and signs of hypercalcemia, include polyuria, polydipsia, anorexia, weight loss, nocturia, conjunctivitis, pancreatitis, photophobia, rhinorrhea, pruritis, hyperthermia, decreased libido, elevated BUN, albuminuria, hypercholesterolemia, elevated ALT (SGPT) and AST (SGOT), ectopic calcification, nephrocalcinosis, hypertension and cardiac arrhythmias.

Active Ingredient/Synonyms

(+)-vitamin D3 | (1S,3Z)-3-[(2e)-2-[(1R,3AR,7as)-7a-methyl-1-[(2R)-6-methylheptan-2-yl]-2,3,3a,5,6,7-hexahydro-1H-inden-4-ylidene]ethylidene]-4-methylidene-cyclohexan-1-ol | (3β,5Z,7E)-9,10-secocholesta-5,7,10(19)-trien-3-ol | (5Z,7E)-(3S)-9,10-secocholesta-5,7,10(19)-trien-3-ol | Activated 7-dehydrocholesterol | Calciol | CC | Colecalciferol | colecalciferolum | Oleovitamin D3 | Vitamin D-3 | Vitamin D3 | Cholecalciferol |

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 nutritional supplementation, also for treating dietary shortage or imbalance.

Mechanism of Action

Biotin is necessary for the proper functioning of enzymes that transport carboxyl units and fix carbon dioxide, and is required for various metabolic functions, including gluconeogenesis, lipogenesis, fatty acid biosynthesis, propionate metabolism, and catabolism of branched-chain amino acids.

Pharmacokinetics

Absorption

Systemic - approximately 50%

Distribution

Metabolism

Elimination

Toxicity

Prolonged skin contact may cause irritation.

Active Ingredient/Synonyms

(+)-cis-Hexahydro-2-oxo-1H-thieno[3,4]imidazole-4-valeric acid | (3AS,4S,6ar)-hexahydro-2-oxo-1H-thieno[3,4-D]imidazole-4-valeric acid | 5-(2-Oxohexahydro-1H-thieno[3,4-D]imidazol-4-yl)pentanoic acid | Biotin | Biotina | Biotine | Biotinum | cis-(+)-Tetrahydro-2-oxothieno[3,4]imidazoline-4-valeric acid | cis-Hexahydro-2-oxo-1H-thieno(3,4)imidazole-4-valeric acid | cis-Tetrahydro-2-oxothieno(3,4-D)imidazoline-4-valeric acid | Coenzyme R | D-(+)-Biotin | D-Biotin | D(+)-Biotin | Vitamin B7 | Vitamin H | Biotin |

Indication

Injection: Prophylactic use immediately after major abdominal surgery to minimize the possibility of paralytic ileus. Intestinal atony causing abdominal distention; postoperative or postpartum retention of flatus, or postoperative delay in resumption of intestinal motility; paralytic ileus. Topical: This medication is used as a moisturizer to treat or prevent dry, rough, scaly, itchy skin and minor skin irritations (e.g., diaper rash, skin burns from radiation therapy).

Mechanism of Action

Dexpanthenol is an alcohol derivative of pantothenic acid, a component of the B complex vitamins and an essential component of a normally functioning epithelium. Dexpanthenol is enzymatically cleaved to form pantothenic acid, which is an essential component of Coenzyme A, which acts as a cofactor in many enzymatic reactions that are important for protein metabolism in the epithelium[A32373]. Dermatological effects of the topical use of dexpanthenol include increased fibroblast proliferation and accelerated re-epithelialization in wound healing. Furthermore, it acts as a topical protectant, moisturizer, and has demonstrated anti-inflammatory properties [A32377].

Pharmacokinetics

Absorption

Dexpanthenol is soluble in water and alcohol, although insoluble in fats and oil based substances. With the appropriate vehicle, Dexpanthenol is easily penetrated into the skin. Rate of penetration and absorption is reduced when Dexpanthenol is administered as an oil/water formula.

Distribution

Dexpanthenol is readily converted to pantothenic acid which is widely distributed into body tissues, mainly as coenzyme A. Highest concentrations are found in the liver, adrenal glands, heart, and kidneys.

Metabolism

Dexpanthenol is readily converted to pantothenic acid which is widely distributed into body tissues, mainly as coenzyme A.

Elimination

Toxicity

Mouse LD50 : 9gm/kg (Intraperitoneal) Mouse: LD50 7gm/kg (Intravenous) Mouse: LD50 15gm/kg (Oral) Rabbit LD50 4gm/kg (Oral)

Active Ingredient/Synonyms

(+)-Panthenol | (2R)-2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethylbutanamide | Bepanthen | Bepanthene | Bepantol | D-panthenol | D-panthenol 50 | D-Pantothenol | D-Pantothenyl alcohol | D(+)-Panthenol | Pantol | Pantothenyl alcohol | Provitamin B | Dexpanthenol |

Indication

For treatment of folic acid deficiency, megaloblastic anemia and in anemias of nutritional supplements, pregnancy, infancy, or childhood.

Mechanism of Action

Folic acid, as it is biochemically inactive, is converted to tetrahydrofolic acid and methyltetrahydrofolate by dihydrofolate reductase. These folic acid congeners are transported across cells by receptor-mediated endocytosis where they are needed to maintain normal erythropoiesis, synthesize purine and thymidylate nucleic acids, interconvert amino acids, methylate tRNA, and generate and use formate. Using vitamin B12 as a cofactor, folic acid can normalize high homocysteine levels by remethylation of homocysteine to methionine via methionine synthetase.

Toxicity

IPR-MUS LD₅₀ 85 mg/kg,IVN-GPG LD₅₀ 120 mg/kg, IVN-MUS LD₅₀ 239 mg/kg, IVN-RAT LD₅₀ 500 mg/kg, IVN-RBT LD₅₀ 410 mg/kg

Active Ingredient/Synonyms

Folacin | Folate | Folic acid | Folsaeure | N-[(4-{[(2-amino-4-oxo-1,4-dihydropteridin-6-yl)methyl]amino}phenyl)carbonyl]-L-glutamic acid | N-Pteroyl-L-glutamic acid | PGA | PteGlu | Pteroyl-L-glutamate | Pteroyl-L-glutamic acid | Pteroyl-L-monoglutamic acid | Pteroylglutamic acid | Vitamin B9 | Vitamin Bc | Vitamin M | Folic Acid |

Indication

Some evidence suggests that NADH might be useful in treating Parkinson's disease, chronic fatigue syndrome, Alzheimer's disease and cardiovascular disease.

Mechanism of Action

NADH is synthesized by the body and thus is not an essential nutrient. It does require the essential nutrient nicotinamide for its synthesis, and its role in energy production is certainly an essential one. In addition to its role in the mitochondrial electron transport chain, NADH is produced in the cytosol. The mitochondrial membrane is impermeable to NADH, and this permeability barrier effectively separates the cytoplasmic from the mitochondrial NADH pools. However, cytoplasmic NADH can be used for biologic energy production. This occurs when the malate-aspartate shuttle introduces reducing equivalents from NADH in the cytosol to the electron transport chain of the mitochondria. This shuttle mainly occurs in the liver and heart.

Pharmacokinetics

Absorption

Unclear how much of an administered dose is absorbed.

Distribution

Metabolism

Elimination

Toxicity

No reports of overdose, however, high doses of NADH (10 mg a day or more) may cause jitteriness, anxiety, and insomnia.

Active Ingredient/Synonyms

1,4-dihydronicotinamide adenine dinucleotide | DPNH | NAD reduced form | Nicotinamide adenine dinucleotide (reduced) | Nicotinamide-adenine dinucleotide, reduced | Reduced nicotinamide adenine diphosphate | Reduced nicotinamide-adenine dinucleotide | NADH |

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 |