Folate metabolism absorption

Certain drugs such as anticonvulsants and oral contraceptives can impair the absorption of folate. Anticonvulsants also increase the rate of folate metabolism. 

Pentamidine is an aromatic diamidine that was initially synthesized in the 1930s in a search for hypoglycemic agents. Because of its antiprotozoal activity, pentamidine has been used extensively for treatment and chemoprophylaxis of African trypanosomiasis. The exact mechanism of action of pentamidine is not known in vitro, it has been found to interfere with folate metabolism, anaerobic glycolysis, oxidative phosphorylation, and nucleic acid replication [1], Pentamidine usually is given parenterally in a dose of 4mg/kg/day as the isethionate salt, the only preparation available in the United States [1], Administration must be parenteral because gastrointestinal absorption is poor. Adverse reactions to pentamidine appear to be dose dependent, in that a 3-g total dose, which usually is reached in the second week of parenteral therapy, frequently causes toxicity [2]. 

Most signs of scurvy can be related to inadequate or abnormal collagen synthesis. Ascorbate enhances prolyl and lysyl hydroxylase activities (Chapter 25). Collagen formed in scorbutic patents is low in hydroxyproline and poorly cross-linked, resulting in skin lesions, bone fractures, and rupture of capillaries and other blood vessels. The absolute amount of collagen made in scorbutic animals may also decrease independently of the hydroxylation defect. The anemia of scurvy may result from a defect in iron absorption or folate metabolism. 

The function of folate binders in folate metabolism remains unclear, except in the case of milk where they have recently been shown to enhance the absorption of folate in breast-fed infants and possibly protect the folate against utilization by intestinal bacteria (C7). The binder may also have a function in sequestering folate from the mother s circulation. It has not been shown to have a role in polyglutamate synthesis nor does it appear to play a part in enabling cells to take up folate on the contrary, Waxman and Schrei-ber (W12) have shown that the binder prevents the uptake of folate by cells in tissue culture. 

There have been other single reports of megaloblastic anemia associated with an apparent abnormality of folate metabolism. One child had a normal serum folate of 6 p,g/liter, an erythrocyte folate of 1480 p.g/liter, and a megaloblastic anemia which responded to treatment with folic acid (VI). Lampkin (Lll) described two sisters with a severe megaloblastic anemia and normal vitamin 6 2 folate levels. Absorption of vitamin 6, 2 normal and both patients excreted an increased amount of formiminoglutamic acid. It was thought that they required both vitamin B 2 and folate to restore normoblastic hemopoiesis. 

Impaired absorption has been found in some patients with malignant disease, but this is probably related to active disease close to or actually involving the small intestine (P3, K9). Little information is available on folate metabolism in patients with hepatic carcinoma and its effect on the recycling of folate in bile. 

R12. Relief, F. P., Heydenrych, J. J., and Murphy, G. P., Aspects of folate metabolism during surgical trauma, with special reference to renal allotransplantation in the baboon Gastric absorption of folate. S. A/r. Med. J. (Suppl., 17 August 1968), 13-16 (1968). 

The possible effects of OCAs on folate metabolism, as indicated by these studies of serum folate concentrations, may therefore be mild but could assume considerable importance in subjects with gastrointestinal disease and decreased absorption of folate, women with marginal dietary folate intake, and those who subsequently become pregnant and then have an increased requirement for folic acid. Studies that followed were warranted by these considerations. 

Little is known about other aspects of folate metabolism, such as the factors that determine plasma clearance, in either normal subjects or users of oral contraceptive steroids. As described earlier, maximum serum folate concentrations after oral folate polyglutamate are lower in contraceptive users than in nonusers, when subjects are not presaturated (S19). This may be due to increased clearance from plasma, because poor absorption was not found. Stephens et al. (S19) felt that this was probably not due to tissue folate depletion because there was no correlation with initial fasting serum folate concentrations. However, erythrocyte folate concentrations were not measured and might have been a better index of tissue saturation with the vitamin. 

At present there are not suflBcient data to decide whether derangements in folate metabolism unrelated to absorption occur in oral contraceptive users, and further research is needed. 

The absorption of folic acid was reduced by about one-third (from 65 to 44.5%) in patients with ulcerative and granulomatous colitis, when compared with healthy subjects, and even further reduced (down to 32%) when sulfasalazine was taken. Another study confirmed that serum folate levels are lower in patients with ulcerative colitis taking sulfasalazine, and that the impairment of the absorption of folates by sulfasalazine was a mechanism in this. Sulfasalazine is also known to interfere with folate metabolism. 

Symptoms of deficiency. Scurvy fatigue, bleeding gums, muscle pain, depression, dry skin, impaired iron absorption, impaired folate metabolism, impaired wound healing. 

An anticonvulsant drug. Among its undesirable side-effects h that of osteomalacia. This is thought to be due to the stimulatior by the drug of hepatic enzymes which inactivate vitamin D resulting in decreased calcium absorption. Phenytoin also in terferes with folate metabolism and this may result in i megaloblastic anaemia. 

Since sulfasalazine inhibits the absorption of folic acid, patients may become folate deficient during longterm therapy. Sulfasalazine decreases the bioavailabiUty of digoxin. Cholestyramine reduces the metabolism of sulfasalazine. Sulfasalazine causes a reversible decrease in sperm counts. Sulfasalazine is safe in pregnancy. 

Folacin bioavailability varies among the vitamers (120,125). Folic acid is more readily available than the naturally occurring food folates but may be less available from fortified foods than in aqueous solution or tablet form. Food folates have been reported to be 30-80% as available as folic acid. Folacin availability, absorption, and metabolism were recently reviewed (20,120,122). 

Rosenburg, I. 1990. Herman award lecture. Folate absorption clinical questions and metabolic answers. Am J Clin Nutr 51 531. 

Folic acid deficiency, unlike vitamin B12 deficiency, is often caused by inadequate dietary intake of folates. Alcoholics and patients with liver disease develop folic acid deficiency because of poor diet and diminished hepatic storage of folates. There is also evidence that alcohol and liver disease interfere with absorption and metabolism of folates. Pregnant women and patients with hemolytic anemia have increased folate requirements and may become folic acid-deficient, especially if their diets are marginal. Evidence implicates maternal folic acid deficiency in the occurrence of fetal neural tube defects, eg, spina bifida. (See Folic Acid Supplementation A Public Health Dilemma.) Patients with malabsorption syndromes also frequently develop folic acid deficiency. Folic acid deficiency is occasionally associated with cancer, leukemia, myeloproliferative disorders, certain chronic skin disorders, and other chronic debilitating diseases. Patients who require renal dialysis also develop folic acid deficiency, because folates are removed from the plasma each time the patient is dialyzed. 

Folic acid deficiency can be caused by drugs that interfere with folate absorption or metabolism. Phenytoin, some other anticonvulsants, oral contraceptives, and isoniazid can cause folic acid deficiency by interfering with folic acid absorption. Other drugs such as methotrexate and, to a lesser extent, trimethoprim and pyrimethamine, inhibit dihydrofolate reductase and may result in a deficiency of folate cofactors and ultimately in megaloblastic anemia. 

The well-known dose-related side effects include gingival hyperplasia (due to altered collagen metabolism), cerebellar-vestibular effects (nystagmus, vertigo, ataxia), behavioural changes (confusion, drowsiness, hallucinations), increased seizure frequency, gastrointestinal disturbances (nausea, anorexia), osteomalacia (due to reduced calcium absorption and increased vitamin D metabolism) and megaloblastic anaemia (due to reduced folate absorption). 

Oxidized folate is not only metabolically dead buyt may even be neurotoxic. For example, a patient with epilepsy who has not had a convulsion in years because dilantin has produced complete control, can be thrown into an immediate convulsion with a megadose of folic acid, because folic acid and dilantin compete for absorption at the brain cell surface, and too much oxidized folic acid will block the ability of the brain cell to take up dilantin, similar to the competition between dilantin and folic acid for uptake by the gutcell (22). 

Antibiotics. Long-term administration of antibiotics could lead to vitamin B6 deficiency, If symptoms of peripheral neuropathy develop (numbness and tingling of the extremities), administer vitamin B6. Sulfasalazine can decrease the absorption of folic acid, and trimethoprim can cause folate deficiency, hence the need to administer folic acid if there is evidence of deficiency. Rifampicin can cause disturbances in vitamin D metabolism and lead to osteomalacia. The absorption of tetracyclines can be reduced by calcium, magnesium, iron and zinc, while this antibiotic could also decrease the absorption of these minerals. This effect is probably least with minocycline and is not confirmed with doxycycline. Doses of minerals and antibiotic should be separated by at least 2 hours. The absorption of quinolones is reduced by cationic and anionic supplements. 

The predominant causes of folate deficiency in non-alcoholics are impaired absorption or metabolism or an increased demand for the vitamin. 

Chronic alcoholism is the major cause of folate deficiency in the United States. Alcoholics generally have poor diets — for example, one liter of whiskey per day. It is not dear if the alcohol induces metabolic defects that interfere with the metabolism and function of folate. Beer docs contain folate, as this product is brewed with yeast, an organism containing high levels tif the vitamin. Wine and hard liquors, on the other hand, contain little or no folate. The elderly may also be at risk for folate deficiency. It is thought that in the elderly the deficiency is due to poor diets rather than age-related defects in the absorption and utilization of folate. 

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