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

1404 By studying the progeny of a genetic cross between a
chloroquine-sensitive clone and a chloroquine-resistant clone,
Wellems, Fidock, and colleagues identified a polymorphic gene
(pfcrt, for P. falciparum chloroquine resistance transporter) that segregates
with chloroquine resistance. Geographically distinct pfcrt
alleles, possessing 4-8 point mutations compared to the invariant
chloroquine-sensitive allele, were found to be highly associated with
chloroquine resistance in clinical field isolates from across the
malaria-endemic areas of the globe (Fidock et al., 2000). Multiple
mutations are needed to confer resistance, including the K76T mutation
that is ubiquitous to chloroquine-resistant strains. The pfcrt gene
encodes a putative transporter that resides in the membrane of the
acidic digestive vacuole, the site of hemoglobin degradation and
chloroquine action. Its physiological function, however, remains
unknown. Chloroquine binding and accumulation studies, with
genetically modified isogenic lines differing in their pfcrt allele, suggest
that mutant pfcrt confers chloroquine resistance by actively
effluxing chloroquine away from its heme target in the digestive vacuole,
seemingly via an energy-dependent process (Sanchez et al.,
2007). Heterologous expression of codon-adjusted pfcrt alleles in
Xenopus laevis oocytes has recently provided compelling evidence
that mutant PfCRT can efflux chloroquine, and has found that this
property was not solely dependent on the K76T mutation (Martin
et al., 2009). Genomic studies suggest that pfcrt has been under
intense selection pressure in recent decades, consistent with its role
as the primary resistance determinant and the prevalence of chloroquine
use in populations exposed to parasites (Mu et al, 2010).
Studies from Malawi have found that mutant pfcrt alleles essentially
disappear upon prolonged cessation of chloroquine use. This implies
that mutant pfcrt alleles can impart a significant fitness cost to the
organism. This cost of fitness results in attrition of mutant forms in
areas where polyclonal infections are common and subjects are sufficiently
immune such that a substantial proportion of infections are
not subject to the pressure of drug selection.
In addition to chloroquine, variant pfcrt alleles may impact
parasite susceptibility to other antimalarials. As an example, the 7G8
allele, representative of pfcrt sequences from South America and the
Pacific region, imparts low-level cross resistance to monodesethylamodiaquine,
the active metabolite of amodiaquine (Sidhu et al.,
2002). Cross-resistance to quinine has also been observed with some
pfcrt alleles in certain genetic backgrounds. In contrast, mutant pfcrt
increases parasite susceptibility to lumefantrine and artemisinin
derivatives, which bodes well for the use of artemether-lumefantrine
in areas where the prevalence of mutant pfcrt is high (Sisowath et al.,
2009). In addition to PfCRT, the P-glycoprotein transporter encoded
by pfmdr1, and other transporters including PfMRP, may play a
modulatory role in chloroquine resistance (Duraisingh and Cowman,
2005, Raj et al., 2009), and the glutathione system also could contribute
(Ginsburg and Golenser, 2003).
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
Absorption, Fate, and Excretion. Chloroquine is well absorbed from
the GI tract and rapidly from intramuscular and subcutaneous sites.
This drug extensively sequesters in tissues, particularly liver, spleen,
kidney, lung, melanin-containing tissues, and, to a lesser extent,
brain and spinal cord. Chloroquine binds moderately (60%) to
plasma proteins and undergoes appreciable biotransformation via
hepatic CYPs to two active metabolites, desethylchloroquine and
bisdesethylchloroquine (Ducharme and Farinotti, 1996). These
metabolites may reach plasma concentrations of 40% and 10% of
that of chloroquine, respectively. The renal clearance of chloroquine
is about half of its total systemic clearance. Unchanged chloroquine
and desethylchloroquine account for >50% and 25% of the urinary
drug products, respectively, and the renal excretion of both compounds
is increased by acidification of the urine.
Both in adults and in children, chloroquine exhibits complex
pharmacokinetics such that plasma levels of the drug shortly after
dosing are determined primarily by the rate of distribution rather
than the rate of elimination (Krishna and White, 1996). Because of
extensive tissue binding, a loading dose is required to achieve effective
concentrations in plasma. After parenteral administration, rapid
entry into the bloodstream together with slow exit from this compartment
can result in transiently high and potentially lethal concentrations
of the drug in plasma. Hence, parenteral chloroquine is given
either slowly by constant intravenous infusion or in small divided
doses by the subcutaneous or intramuscular route. Chloroquine is
safer when given orally because the rates of absorption and distribution
are more closely matched. Peak plasma levels are achieved in
~3-5 hours after dosing by this route. The t 1/2
of chloroquine
increases from a few days to weeks as plasma levels decline, reflecting
release of drug from extensive tissue stores. The terminal t 1/2
ranges from 30 to 60 days, and traces of the drug can be found in the
urine for years after a therapeutic regimen.
Therapeutic Uses. Chloroquine is highly effective against
the erythrocytic forms of P. vivax, P. ovale, P. malariae,
P. knowlesi, and chloroquine-sensitive strains of P. falciparum.
For infections caused by P. ovale and P. malariae,
it remains the agent of choice for chemoprophylaxis
and treatment. Chloroquine is also widely used to treat
P. vivax; however, as mentioned earlier, resistant strains
have been detected, mostly in Asia and the Pacific region.
For P. falciparum this drug has been largely replaced by
artemisinin-based combination therapies (Eastman and
Fidock, 2009). Gametocytocidal activity has been
reported for the four main Plasmodium species infecting
humans, with activity against P. falciparum restricted to
immature gametocytes exposed to concentrations that are
several fold higher than those effective against drug-sensitive
asexual blood stage P. falciparum parasites. The
drug has no activity against latent hypnozoite forms of P.
vivax or P. ovale.
Chloroquine is inexpensive and safe, but its usefulness has
declined across most malaria-endemic regions of the world because
of the spread of chloroquine-resistant P. falciparum. Except in areas
where resistant strains of P. vivax are reported, chloroquine is very
effective in chemoprophylaxis or treatment of acute attacks of
malaria caused by P. vivax, P. ovale, and P. malariae (Table 49–3).
Chloroquine has no activity against primary or latent liver stages of
the parasite. To prevent relapses in P. vivax and P. ovale infections,
primaquine can be given either with chloroquine or used after a
patient leaves an endemic area. Chloroquine rapidly controls the
clinical symptoms and parasitemia of acute malarial attacks. Most
patients become completely afebrile within 24-48 hours after receiving