A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Fansidar Pharmacology, Pharmacokinetics, Studies, Metabolism - Sulfadoxine and Pyrimethamine
Fansidar Pharmacology, Pharmacokinetics, Studies, Metabolism - Sulfadoxine and Pyrimethamine
CLINICAL PHARMACOLOGY
Microbiology
Mechanism of Action: Sulfadoxine and pyrimethamine,
the constituents of Fansidar, are folic acid antagonists. Sulfadoxine inhibits
the activity of dihydropteroate synthase whereas pyrimethamine inhibits dihydrofolate
reductase.
Activity in vitro: Sulfadoxine and pyrimethamine
are active against the asexual erythrocytic stages of Plasmodium falciparum.
Fansidar may also be effective against strains of P. falciparum resistant
to chloroquine.
Drug Resistance: Strains of P. falciparum with
decreased susceptibility to sulfadoxine and /or pyrimethamine can be selected
in vitro or in vivo. P. falciparum malaria that is clinically
resistant to Fansidar occurs frequently in parts of Southeast Asia and South
America, and is also prevalent in East and Central Africa. Therefore, Fansidar
should be used with caution in these areas. Likewise, Fansidar may not be effective
for treatment of recrudescent malaria that develops after prior therapy (or
prophylaxis) with Fansidar.
PHARMACOKINETICS
Absorption
After administration of 1 tablet, peak plasma levels for pyrimethamine
(approximately 0.2 mg/L) and for sulfadoxine (approximately 60 mg/L) are reached
after about 4 hours.
Distribution
The volume of distribution for sulfadoxine and pyrimethamine
is 0.14 L/kg and 2.3 L/kg, respectively. Patients taking 1 tablet a week (recommended
adult dose for malaria prophylaxis) can be expected to have mean steady state
plasma concentrations of about 0.15 mg/L for pyrimethamine after about four
weeks and about 98 mg/L for sulfadoxine after about seven weeks. Plasma protein
binding is about 90% for both pyrimethamine and sulfadoxine. Both pyrimethamine
and sulfadoxine cross the placental barrier and pass into breast milk.
Metabolism
About 5% of sulfadoxine appears in the plasma as acetylated
metabolite, about 2 to 3% as the glucuronide. Pyrimethamine is transformed to
several unidentified metabolites.
Elimination
A relatively long elimination half-life is characteristic of
both components. The mean values are about 100 hours for pyrimethamine and about
200 hours for sulfadoxine. Both pyrimethamine and sulfadoxine are eliminated
mainly via the kidneys.
Characteristics in Patients
In malaria patients, single pharmacokinetic parameters may
differ from those in healthy subjects, depending on the population concerned.
In patients with renal insufficiency, delayed elimination of the components
of Fansidar must be anticipated.
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