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

Pteroyl
Monoheptaglutamate
1093
3 6
O
COOH
N 4
N
5 CH 2
9
NH
10
CO NH CH
H 2 N
2 1
N N
CH 2
CH 2
CO NH X 0–7
Position Radical
N 5 —CH 3
N 5 —CHO
N 10 —CHO
N 5,10 — CH—
N 5,10 —CH 2 —
N 5 —CHNH
N 10 —CH 2 OH
Congener
CH 3 H 4 PteGlu
5-CHOH 4 PteGlu
10-CHOH 4 PteGlu
5,10-CHH 4 PteGlu
5,10-CH 2 H 4 PteGlu
CHNHH 4 PteGlu
CH 2 OHH 4 PteGlu
Methyltetrahydrofolate
Folinic acid (citrovorum factor)
10-Formyltetrahydrofolate
5,10-Methenyltetrahydrofolate
5,10-Methylenetetrahydrofolate
Formiminotetrahydrofolate
Hydroxymethyltetrahydrofolate
Figure 37–9. The structures and nomenclature of pteroylglutamic acid (folic acid) and its congeners. X represents additional residues
of glutamate; polyglutamates are the storage and active forms of the vitamin. The subscript that designates the number of residues of
glutamate is frequently omitted because this number is variable.
CHAPTER 37
HEMATOPOIETIC AGENTS
reactions catalyzed by ribotide transformylases: the formylation of
glycinamide ribonucleotide and the formylation of 5-aminoimidazole-
4-carboxamide ribonucleotide. By these reactions, carbon atoms at
positions 8 and 2, respectively, are incorporated into the growing
purine ring.
Utilization or generation of formate. This reversible reaction uses
H 4
PteGlu and 10-CHOH 4
PteGlu.
Daily Requirements. Many food sources are rich in
folates, especially fresh green vegetables, liver, yeast,
and some fruits. However, lengthy cooking can destroy
up to 90% of the folate content of such food.
Generally, a standard U.S. diet provides 50-500 μg of
absorbable folate per day, although individuals with high intakes of
fresh vegetables and meats will ingest as much as 2 mg per day. In
the normal adult, the recommended daily intake is 400 μg; pregnant
or lactating women and patients with high rates of cell turnover (such
as patients with a hemolytic anemia) may require 500-600 μg or
more per day. For the prevention of neural tube defects, a daily intake
of at least 400 μg of folate in food or in supplements beginning a
month before pregnancy and continued for at least the first trimester
is recommended. Folate supplementation also is being considered
in patients with elevated levels of plasma homocysteine.
Absorption, Distribution, and Elimination. As with
vitamin B 12
, the diagnosis and management of deficiencies
of folic acid depend on an understanding of the
transport pathways and intracellular metabolism of the
vitamin (Figure 37–10). Folates present in food are
largely in the form of reduced polyglutamates, and
absorption requires transport and the action of a
pteroylglutamyl carboxypeptidase associated with
mucosal cell membranes. The mucosae of the duodenum
and upper part of the jejunum are rich in dihydrofolate
reductase and can methylate most or all of the
reduced folate that is absorbed. Because most absorption
occurs in the proximal portion of the small intestine,
it is not unusual for folate deficiency to occur
when the jejunum is diseased. Both nontropical and
tropical sprue are common causes of folate deficiency
and megaloblastic anemia.
Once absorbed, folate is transported rapidly to tissues as
CH 3
H 4
PteGlu. Although certain plasma proteins do bind folate
derivatives, they have a greater affinity for nonmethylated analogs.
The role of such binding proteins in folate homeostasis is not well
understood. An increase in binding capacity is detectable in folate
deficiency and in certain disease states, such as uremia, cancer, and
alcoholism, but how binding affects transport and tissue supply
requires further investigation.
A constant supply of CH 3
H 4
PteGlu is maintained by food and
by an enterohepatic cycle of the vitamin. The liver actively reduces
and methylates PteGlu (and H 2
or H 4
PteGlu) and then transports the
CH 3
H 4
PteGlu into bile for reabsorption by the gut and subsequent
delivery to tissues. This pathway may provide ≥200 μg of folate each
day for recirculation to tissues. The importance of the enterohepatic
cycle is suggested by animal studies that show a rapid reduction of
the plasma folate concentration after either drainage of bile or ingestion
of alcohol, which apparently blocks the release of CH 3
H 4
PteGlu
from hepatic parenchymal cells.
Folate Deficiency. Folate deficiency is a common complication
of diseases of the small intestine that interferes
with the absorption of folate from food and the recirculation
of folate through the enterohepatic cycle. In acute