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

1400 The 2,4-diaminopyrimidines more potently inhibit
the Plasmodium dihydrofolate reductase compared to
the mammalian enzyme. Unlike its counterpart in
human cells, the malarial dihydrofolate reductase
resides on the same polypeptide chain as thymidylate
synthase and, importantly, protein production is not
increased in response to inhibition. The latter property
favors the selective anti-plasmodial toxicity of
pyrimethamine (Zhang and Rathod, 2002).
Synergy of pyrimethamine and the sulfonamides
or sulfones results from inhibition of two key metabolic
steps in folate biosynthesis in the parasite:
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
• the utilization of p-aminobenzoic acid for the synthesis
of dihydropteroic acid, which is catalyzed by
dihydropteroate synthase and inhibited by sulfonamides
• the reduction of dihydrofolate to tetrahydrofolate,
which is catalyzed by dihydrofolate reductase and
inhibited by pyrimethamine (Figure 52–2).
Dietary p-aminobenzoic acid or folate may affect the therapeutic
response to antifolates. Both of these metabolites can be imported
by the malarial parasite and can reduce drug efficacy substantially
(Hyde, 2007). Resistance to pyrimethamine has developed in regions
of prolonged or extensive drug use and can be attributed to mutations
in dihydrofolate reductase that decrease the binding affinity of
pyrimethamine (Gregson and Plowe, 2005). Interestingly, the pattern of
amino acid substitutions is different in parasites resistant to cycloguanil,
even though cross-resistance can occur between these structurally
related inhibitors of plasmodial dihydrofolate reductase. The key mutation
associated with pyrimethamine resistance is the substitution of
asparagine for serine at codon 108 (S108N). The stepwise accumulation
of additional single-amino-acid changes at codons 51, 59, and 164
is associated with progressively increasing resistance, as determined
with P. falciparum isolates and with recombinant proteins. The triple
mutant N51I/C59R/S108N (predominant in Africa) and the quadruple
mutant N51I/C59R/S108N/I164L (predominant in Southeast Asia)
exhibit high levels of pyrimethamine resistance and contribute to
pyrimethamine-sulfadoxine therapeutic failure. Remarkably, studies
exploring the mutational trajectories leading to the most resistant
quadruple mutant N51I/C59R/S108N/I164L suggest a specific ordering
of mutational events that balance the acquisition of resistance with
the maintenance of pathogen fitness (Lozovsky et al., 2009). These
studies also suggest that this quadruple mutant is substantially less fit
in the absence of drugs when compared to its wild-type counterpart.
Compensatory mechanisms might therefore be necessary to alleviate
this fitness cost. An increase in the number of copy of the GTP
cyclohydrolase I gene, which encodes the first enzyme in the
Plasmodium folate biosynthesis pathway, is closely associated with
the dihydrofolate reductase I164L mutation, suggesting a potential
compensatory function (Nair et al., 2008).
Absorption, Fate, and Distribution. After oral administration,
pyrimethamine is slowly but completely absorbed, reaching peak
plasma levels in 2-6 hours. The compound is significantly distributed
in the tissues and is ~90% bound to plasma proteins (German and
Aweeka, 2008). Pyrimethamine is slowly eliminated from plasma
with a t 1/2
of 85-100 hours. Concentrations that are suppressive for
responsive Plasmodium strains remain in the blood for ~2 weeks,
but levels are lower in patients with active infection. Several metabolites
of pyrimethamine appear in the urine; however, their identities
and antimalarial properties have not been fully characterized.
Pyrimethamine also enters the milk of nursing mothers.
Therapeutic Uses. Pyrimethamine-sulfadoxine is no
longer recommended for the treatment of uncomplicated
malaria or for chemoprophylaxis due to increasing
drug resistance. However, for those living in malariaendemic
areas, some still recommend it for the intermittent
preventive treatment of malaria in pregnancy, and it
is being evaluated for intermittent preventive treatment in
infants (Aponte et al., 2009). Pyrimethamine is typically
administered with either a sulfonamide or sulfone to
enhance its antifolate activity. Most malaria-endemic
areas currently have a high prevalence of pyrimethamineresistant
parasites.
Toxicity, Precautions, and Contraindications. Antimalarial
doses of pyrimethamine alone cause minimal toxicity
except for occasional skin rashes and reduced
hematopoiesis. Excessive doses can produce a megaloblastic
anemia, resembling that of folate deficiency,
which responds readily to drug withdrawal or treatment
with folinic acid. At high doses, pyrimethamine is teratogenic
in animals, and in humans the related combination,
trimethoprim-sulfamethoxazole, may cause birth
defects (Hernandez-Diaz et al., 2000).
Sulfonamides or sulfones, rather than pyrimethamine, usually
account for the toxicity associated with coadministration of
these antifolate drugs. The combination of pyrimethamine and sulfadoxine
is no longer recommended for malaria chemoprophylaxis
because in ~1 in 5000 to 1 in 8000 individuals, this combination
causes severe and even fatal cutaneous reactions, such as erythema
multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis.
It has also been associated with serum sickness–type reactions,
urticaria, exfoliative dermatitis, and hepatitis. Pyrimethamine-sulfadoxine
is contraindicated for individuals with previous reactions to
sulfonamides, for lactating mothers, and for infants <2 months of
age. Administration of pyrimethamine with dapsone (MALOPRIM), a
drug combination unavailable in the U.S., has occasionally been
associated with agranulocytosis.
PROGUANIL
History. Proguanil is the common name for chloroguanide, a
biguanide derivative that emerged in 1945 as a product of British
antimalarial research. The antimalarial activity of proguanil eventually
was ascribed to cycloguanil, a cyclic triazine metabolite and
selective inhibitor of the bifunctional plasmodial dihydrofolate
reductase-thymidylate synthetase that is crucial for parasite de novo