DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

1094 DIET
Liver
disease and for venous thrombosis, the role of folate as a methyl
donor in the homocysteine-to-methionine conversion is getting
CH 3 H 4 PteGlu 1-8 CH 3 H 4 PteGlu 5
1
increased attention. Patients who are heterozygous for one or another
PteGlu 1
enzymatic defect and have high normal to moderate elevations of
CH 3 H 4 PteGlu 1 PteGlu 1
plasma homocysteine may improve with folic acid therapy.
Folate deficiency is recognized by its impact on the
4 H 2 or H 4 PteGlu 1 hematopoietic system. As with vitamin B 12
, this fact reflects the
2 3
increased requirement associated with high rates of cell turnover.
Hydrolysis
The megaloblastic anemia that results from folate deficiency cannot
Plasma binding
Reduction
protein
be distinguished from that caused by vitamin B 12
deficiency. This
Methylation
finding is to be expected because of the final common pathway of the
-CH 3
major intracellular metabolic roles of the two vitamins. At the same
CH 3 H 4 PteGlu 1 H 2 or H 4 PteGlu 1 time, folate deficiency is rarely if ever associated with neurological
5 B 12
abnormalities. Thus the observation of characteristic abnormalities
in vibratory and position sense and in motor and sensory pathways
CH 3 H 4 PteGlu 5
is incompatible with an isolated deficiency of folic acid.
Tissue
SECTION IV
INFLAMMATION. IMMUNOMODULATION, AND HEMATOPOIESIS
Figure 37–10. Absorption and distribution of folate derivatives.
Dietary sources of folate polyglutamates are hydrolyzed to the
monoglutamate, reduced, and methylated to CH 3
H 4
PteGlu 1
during
gastrointestinal transport. Folate deficiency commonly results
from (1) inadequate dietary supply and (2) small intestinal disease.
In patients with uremia, alcoholism, or hepatic disease there
may be defects in (3) the concentration of folate binding proteins
in plasma and (4) the flow of CH 3
H 4
PteGlu 1
into bile for reabsorption
and transport to tissue (the folate enterohepatic cycle).
Finally, vitamin B 12
deficiency will (5) “trap” folate as
CH 3
H 4
PteGlu, thereby reducing the availability of H 4
PteGlu 1
for
its essential roles in purine and pyrimidine synthesis.
or chronic alcoholism, daily intake of folate in food may
be severely restricted, and the enterohepatic cycle of the
vitamin may be impaired by toxic effects of alcohol on
hepatic parenchymal cells; this is the most common
cause of folate-deficient megaloblastic erythropoiesis.
However, it also is the most amenable to therapy, inasmuch
as the reinstitution of a normal diet is sufficient to
overcome the effect of alcohol. Disease states characterized
by a high rate of cell turnover, such as hemolytic
anemias, also may be complicated by folate deficiency.
Additionally, drugs that inhibit dihydrofolate reductase
(e.g., methotrexate and trimethoprim) or that interfere
with the absorption and storage of folate in tissues (e.g.,
certain anticonvulsants and oral contraceptives) can
lower the concentration of folate in plasma and may
cause a megaloblastic anemia (Scott and Weir, 1980).
Folate deficiency has been implicated in the incidence of neural
tube defects, including spina bifida, encephaloceles, and anencephaly.
This is true even in the absence of folate-deficient anemia
or alcoholism. A less-than-adequate intake of folate also can result
in elevations in plasma homocysteine (Green and Miller, 1999).
Because even moderate hyperhomocysteinemia is considered an
independent risk factor for coronary artery and peripheral vascular
After deprivation of folate, megaloblastic anemia develops much
more rapidly than it does following interruption of vitamin B 12
absorption (e.g., gastric surgery). This observation reflects the fact
that body stores of folate are limited. Although the rate of induction
of megaloblastic erythropoiesis may vary, a folate-deficiency state
may appear in 1-4 weeks, depending on the individual’s dietary
habits and stores of the vitamin.
Folate deficiency is best diagnosed from measurements of
folate in plasma and in red cells. However, an empirical trial of folate
in cases of suspected deficiency has been proposed as more cost
effective (Robinson and Mladenovic, 2001). Indeed, the concentration
of folate in plasma is extremely sensitive to changes in dietary
intake of the vitamin and the influence of inhibitors of folate metabolism
or transport, such as alcohol. Normal folate concentrations in
plasma range from 9-45 nmol (4-20 ng/mL); <9 nmol is considered
folate deficient. The plasma folate concentration rapidly falls to values
indicative of deficiency within 24-48 hours of steady ingestion
of alcohol (Eichner and Hillman 1973). The plasma folate concentration
will revert quickly to normal once such ingestion is stopped,
even while the marrow is still megaloblastic. Such rapid fluctuations
detract from the clinical usefulness of the plasma folate concentration.
The amount of folate in red cells or the adequacy of stores in
lymphocytes (as measured by the deoxyuridine suppression test)
may be used to diagnose a longstanding deficiency of folic acid. A
positive result on either test shows that the deficiency must have
existed for a sufficient time to allow the production of a population
of cells with deficient folate stores.
Folic acid is marketed as oral tablets containing pteroylglutamic
acid or L-methylfolate, as an aqueous solution for injection
(5 mg/mL), and in combination with other vitamins and minerals.
Folinic acid (leucovorin calcium, citrovorum factor) is the
5-formyl derivative of tetrahydrofolic acid. The principal therapeutic
uses of folinic acid are to circumvent the inhibition of dihydrofolate
reductase as a part of high-dose methotrexate therapy and to
potentiate fluorouracil in the treatment of colorectal cancer (Chapter
61). It also has been used as an antidote to counteract the toxicity of
folate antagonists such as pyrimethamine or trimethoprim. Although
it can be used to treat any folate-deficient state, folinic acid provides
no advantage over folic acid, is more expensive, and therefore is
not recommended. A single exception is the megaloblastic anemia
associated with congenital dihydrofolate reductase deficiency.