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

due to decreased production of erythropoietin. Patients with low
plasma erythropoietin may respond to administration of recombinant
erythropoietin. Anemia reverses slowly following cessation of
therapy. Headache, nausea, vomiting, malaise, weight loss, and
phlebitis at peripheral infusion sites are common. Thrombocytopenia
or mild leukopenia is observed rarely. Hepatotoxicity is not firmly
established with any amphotericin B formulation. Arachnoiditis has
been observed as a complication of injecting C-AMB into the CSF.
Flucytosine
Chemistry. Flucytosine is 5-fluorocytosine, a fluorinated pyrimidine
related to fluorouracil and floxuridine.
Mechanism of Action. All susceptible fungi are capable of deaminating
flucytosine to 5-fluorouracil (Figure 57–2), a potent
antimetabolite that is used in cancer chemotherapy (Chapter 61).
Fluorouracil is metabolized first to 5-fluorouracil-ribose monophosphate
(5-FUMP) by the enzyme uracil phosphoribosyl transferase
(UPRTase; also called uridine monophosphate pyrophosphorylase).
As in mammalian cells, 5-FUMP then is either incorporated into
RNA (via synthesis of 5-fluorouridine triphosphate) or metabolized
to 5-fluoro-2-deoxyuridine-5-monophosphate (5-FdUMP), a
potent inhibitor of thymidylate synthetase. DNA synthesis is
impaired as the ultimate result of this latter reaction. The selective
action of flucytosine is due to the lack of cytosine deaminase
in mammalian cells, which prevents metabolism to fluorouracil.
Antifungal Activity. Flucytosine has clinically useful activity
against Cryptococcus neoformans, Candida spp., and the agents of
chromoblastomycosis. Within these species, determination of susceptibility
in vitro has been extremely dependent on the method
employed, and susceptibility testing performed on isolates obtained
prior to treatment has not correlated with clinical outcome.
Fungal Resistance. Drug resistance arising during therapy (secondary
resistance) is an important cause of therapeutic failure when flucytosine
is used alone for cryptococcosis and candidiasis. In chromoblastomycosis,
resurgence of lesions after an initial response has led to the presumption
of secondary drug resistance. In isolates of Cryptococcus and
Candida species, secondary drug resistance has been accompanied by
a change in the minimal inhibitory concentration from <2.5 μg/mL to
>360 μg/mL. The mechanism for this resistance can be loss of the permease
necessary for cytosine transport or decreased activity of either
UPRTase or cytosine deaminase (Figure 57–2). In Candida albicans,
substitution of thymidine for cytosine at nucleotide 301 in the gene
encoding UPRTase (FURl) causes a cysteine to become an arginine,
modestly increasing flucytosine resistance (Dodgson et al., 2004).
Flucytosine resistance is further increased if both FURl alleles in the
diploid fungus are mutated.
Absorption, Distribution, and Excretion. Flucytosine is absorbed rapidly
and well from the GI tract. It is widely distributed in the body,
5-FU
5-FUMP
uPRTase
ribonucleotide
reductase
dUMP
cytosine
deaminase
5-FUDP
5-FdUMP
thymidylate
synthase
Flucytosine
5-FUTP
RNA
dTMP
Figure 57–2. Action of flucytosine in fungi. Flucytosine is transported
by cytosine permease into the fungal cell, where it is
deaminated to 5-fluorouracil (5-FU). The 5-FU is then converted
to 5-fluorouracil-ribose monophosphate (5-FUMP) and
then is either converted to 5-fluorouridine triphosphate
(5-FUTP) and incorporated into RNA or converted by ribonucleotide
reductase to 5-fluoro-2-deoxyuridine-5-monophosphate
(5-FdUMP), which is a potent inhibitor of thymidylate synthase.
5-FUDP, 5-fluorouridine-5-diphosphate; dUMP, deoxyuridine-
5-monophosphate; dTMP, deoxythymidine-5-monophosphate.
with a volume of distribution that approximates total body water,
and is minimally bound to plasma proteins. The peak plasma concentration
in patients with normal renal function is ~70-80 μg/mL,
achieved 1-2 hours after a dose of 37.5 mg/kg. Approximately 80%
of a given dose is excreted unchanged in the urine; concentrations
in the urine range from 200-500 μg/mL. The t 1/2
of the drug is 3-6
hours in normal individuals. In renal failure, the t 1/2
may be as long
as 200 hours. The clearance of flucytosine is approximately equivalent
to that of creatinine. Reduction of dosage is necessary in patients
with decreased renal function, and concentrations of drug in plasma
should be measured periodically. Peak concentrations should range
between 50 and 100 μg/mL. Flucytosine is cleared by hemodialysis,
and patients undergoing such treatment should receive a single dose
of 37.5 mg/kg after dialysis; the drug also is removed by peritoneal
dialysis.
Flucytosine concentration in CSF is ~65-90% of that found
simultaneously in the plasma. The drug also appears to penetrate
into the aqueous humor.
Therapeutic Uses. Flucytosine (ANCOBON) is given orally at 50-150
mg/kg per day, in four divided doses at 6-hour intervals. Dosage must
be adjusted for decreased renal function. Flucytosine is used predominantly
in combination with amphotericin B. Flucytosine caused no
added toxicity when added to 0.7 mg/kg of amphotericin B for the initial
2 weeks of therapy of cryptococcal meningitis in AIDS patients.
Although the CSF colony count diminished more rapidly with combination
therapy, there was no apparent impact on mortality or morbidity
(van der Horst et al., 1997). An all-oral regimen of flucytosine
plus fluconazole also has been advocated for therapy of AIDS patients
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CHAPTER 57
ANTIFUNGAL AGENTS