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

elements formed by amplification of DHFR genes in response to
methotrexate treatment) or in stably integrated, homogeneously
staining chromosomal regions or amplicons. First identified as an
explanation for resistance to methotrexate (Schimke et al., 1978),
gene amplification of a target protein has since been implicated in the
resistance to many antitumor agents, including 5-FU and pentostatin
(2′-deoxycoformycin) and has been observed in patients with lung
cancer (Curt et al., 1985) and leukemia. Impaired transport and
polyglutamation have been implicated as mechanisms of resistance
in childhood leukemia.
To overcome resistance, high doses of methotrexate may permit
entry of the drug into transport-defective cells and may permit
the intracellular accumulation of methotrexate in concentrations that
inactivate high levels of DHFR.
The understanding of resistance to pemetrexed is incomplete.
In various cell lines, resistance to this agent seems to arise from loss
of influx transport, TS amplification, changes in purine biosynthetic
pathways, or loss of polyglutamation.
Absorption, Fate, and Excretion. Methotrexate is readily absorbed
from the GI tract at doses of <25 mg/m 2 , but larger doses are absorbed
incompletely and are routinely administered intravenously. Peak concentrations
of 1-10 μM in the plasma are obtained after doses of
25-100 mg/m 2 , and concentrations of 0.1-1 mM are achieved after
high-dose infusions of 1.5-20 g/m 2 . After intravenous administration,
the drug disappears from plasma in a triphasic fashion (Sonneveld
et al., 1986). The rapid distribution phase is followed by a second
phase, which reflects renal clearance (t 1/2
of ~2-3 hours). A third
phase has a t 1/2
of ~8-10 hours. This terminal phase of disappearance,
if unduly prolonged by renal failure, may be responsible for major
toxic effects of the drug on the marrow, GI epithelium, and skin.
Distribution of methotrexate into body spaces, such as the pleural or
peritoneal cavity, occurs slowly. However, if such spaces are
expanded (e.g., by ascites or pleural effusion), they may act as a site
of storage and slow release of the drug, resulting in prolonged elevation
of plasma concentrations and more severe bone marrow toxicity.
Approximately 50% of methotrexate binds to plasma proteins
and may be displaced from plasma albumin by a number of
drugs, including sulfonamides, salicylates, tetracycline, chloramphenicol,
and phenytoin; caution should be used if these drugs are
given concomitantly. Up to 90% of a given dose is excreted
unchanged in the urine within 48 hours, mostly within the first
8-12 hours. Metabolism of methotrexate in humans usually is minimal.
After high doses, however, metabolites are readily detectable;
these include 7-hydroxy-methotrexate, which is potentially nephrotoxic.
Renal excretion of methotrexate occurs through a combination
of glomerular filtration and active tubular secretion. Therefore,
the concurrent use of drugs that reduce renal blood flow (e.g., nonsteroidal
anti-inflammatory agents), that are nephrotoxic (e.g., cisplatin),
or that are weak organic acids (e.g., aspirin, piperacillin) can
delay drug excretion and lead to severe myelosuppression. Particular
caution must be exercised in treating patients with renal insufficiency.
In such patients, the dose should be adjusted in proportion to decreases
in renal function, and high-dose regimens should be avoided.
Methotrexate is retained in the form of polyglutamates for
long periods—for example, for weeks in the kidneys and for several
months in the liver.
It is important to emphasize that concentrations of methotrexate
in CSF are only 3% of those in the systemic circulation at steady
state; hence, neoplastic cells in the CNS probably are not killed by
standard dosage regimens. When high doses of methotrexate are
given (>1.5 g/m 2 ; see “Therapeutic Uses”), cytotoxic concentrations
of methotrexate reach the CNS.
Pharmacogenetics may influence the response to antifolates
and their toxicity. The C677T substitution in methylenetetrahydrofolate
reductase reduces the activity of the enzyme that generates
methylenetetrahydrofolate, the cofactor for TS, and thereby
increases methotrexate toxicity (Pullarkat et al., 2001). The presence
of this polymorphism in leukemic cells confers increased sensitivity
to methotrexate and might also modulate the toxicity and therapeutic
effect of pemetrexed, a predominant TS inhibitor. Likewise, polymorphisms
in the promoter region of TS govern the translation
efficiency of this message and, by governing the intracellular levels
of TS, modulate the response and toxicity of both antifolates (Pui et
al., 2004) and fluoropyrimidines.
Therapeutic Uses. Methotrexate (Amethopterin; RHEUMATREX, TREX-
ALL, others) has been used in the treatment of severe, disabling psoriasis
in doses of 2.5 mg orally for 5 days, followed by a rest period
of at least 2 days, or 10-25 mg intravenously weekly. It also is used
at low dosage to induce remission in refractory rheumatoid arthritis
(Hoffmeister, 1983). Awareness of the pharmacology, toxic potential,
and drug interactions associated with methotrexate is a prerequisite
for its use in these non-neoplastic disorders.
Methotrexate is a critical drug in the management of acute
lymphoblastic leukemia (ALL) in children. High-dose methotrexate
is of great value in remission induction and consolidation and in the
maintenance of remissions in this highly curable disease. A 6- to
24-hour infusion of relatively large doses of methotrexate may be
employed every 2-4 weeks (≥1-7.5 g/m 2 ) but only when leucovorin
rescue follows within 24 hours of the methotrexate infusion. Such
regimens produce cytotoxic concentrations of drug in the CSF and
protect against leukemic meningitis. For maintenance therapy, it is
administered weekly in doses of 20 mg/m 2 orally. Outcome of treatment
in children correlates inversely with the rate of drug clearance.
During methotrexate infusion, high steady-state levels are associated
with a lower leukemia relapse rate (Pui et al., 2004).
Methotrexate is of limited value in adults with AML, except for treatment
and prevention of leukemic meningitis. The intrathecal administration
of methotrexate has been employed for treatment or
prophylaxis of meningeal leukemia or lymphoma and for treatment
of meningeal carcinomatosis. This route of administration achieves
high concentrations of methotrexate in the CSF and also is effective
in patients whose systemic disease has become resistant to
methotrexate. The recommended intrathecal dose in all patients
>3 years of age is 12 mg (Bleyer, 1978). The dose is repeated every
4 days until malignant cells no longer are evident in the CSF.
Leucovorin may be administered to counteract the potential toxicity
of methotrexate that escapes into the systemic circulation, although
this generally is not necessary. Because methotrexate administered
into the lumbar space distributes poorly over the cerebral convexities,
the drug may be given via an intraventricular Ommaya reservoir in
the treatment of active intrathecal disease. Methotrexate is of established
value in choriocarcinoma and related trophoblastic tumors of
women; cure is achieved in ~75% of advanced cases treated sequentially
with methotrexate and dactinomycin and in >90% when early
diagnosis is made. In the treatment of choriocarcinoma, 1 mg/kg of
methotrexate is administered intramuscularly every other day for
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CHAPTER 61
CYTOTOXIC AGENTS