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

1714 As discussed in “Drug Resistance” under “Vinca Alkaloids,”
multidrug resistance is observed in tumor cell populations exposed to
anthracyclines. Attempts to reverse or prevent the emergence of resistance
through the simultaneous use of inhibitors of the P-glycoprotein
(Ca ++ channel blockers, steroidal compounds, and others) have yielded
inconclusive results, primarily due to confounding effects of these
inhibitors on anthracycline pharmacokinetics and metabolism.
Anthracyclines also are exported from tumor cells by members of the
MRP transporter family and by the breast cancer resistance protein, a
“half” transporter (Doyle et al., 1998). Other biochemical changes in
resistant cells include increased glutathione peroxidase activity,
decreased activity or mutation of topoisomerase II, and enhanced ability
to repair DNA strand breaks.
Absorption, Fate, and Excretion. Daunorubicin, doxorubicin,
epirubicin, and idarubicin usually are administered intravenously
and are cleared by a complex pattern of hepatic metabolism and biliary
excretion. The plasma disappearance curves for doxorubicin and
daunorubicin are multiphasic, with a terminal t 1/2
of 30 hours. All
anthracyclines are converted to an active alcohol intermediate that
plays a variable role in their therapeutic activity. Idarubicin has a
t 1/2
of 15 hours, and its active metabolite, idarubicinol, has a t 1/2
of
40 hours. The drugs rapidly enter the heart, kidneys, lungs, liver,
and spleen. They do not cross the blood-brain barrier.
Daunorubicin and doxorubicin are eliminated by metabolic
conversion to a variety of aglycones and other inactive products.
Idarubicin is primarily metabolized to idarubicinol, which accumulates
in plasma and likely contributes significantly to its activity.
Clearance of anthracyclines and their active alcohol metabolites is
delayed in the presence of hepatic dysfunction, and at least a 50%
initial reduction in dose should be considered in patients with abnormal
serum bilirubin levels (Twelves et al., 1998).
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Therapeutic Use
Idarubicin. The recommended dosage for idarubicin (IDAMYCIN PFS)
is 12 mg/m 2 /day for 3 days by intravenous injection in combination
with cytarabine. Slow injection over 10-15 minutes is recommended
to avoid extravasation, as with other anthracyclines. It has less cardiotoxicity
than the other anthracyclines.
Daunorubicin. Daunorubicin (daunomycin, rubidomycin; CERU-
BIDINE, others) is available for intravenous use. The recommended
dosage is 25-45 mg/m 2 /day for 3 days. The agent is administered
with appropriate care to prevent extravasation, because severe local
vesicant action may result. Total doses of >1000 mg/m 2 are associated
with a high risk of cardiotoxicity. Patients should be advised
that daunorubicin may impart a red color to the urine.
Daunorubicin and idarubicin also are used in the treatment
of AML in combination with Ara-C.
Clinical Toxicities. The toxic manifestations of daunorubicin as well
as idarubicin include bone marrow depression, stomatitis, alopecia,
GI disturbances, and rash. Cardiac toxicity is a peculiar adverse
effect observed with these agents. It is characterized by tachycardia,
arrhythmias, dyspnea, hypotension, pericardial effusion, and congestive
heart failure poorly responsive to digitalis (see “Clinical
Toxicities” under “Doxorubicin”).
Doxorubicin
Therapeutic Uses. Doxorubicin is available for intravenous use. The
recommended dose is 60-75 mg/m 2 , administered as a single rapid
intravenous infusion that is repeated after 21 days. Care should be
taken to avoid extravasation, because severe local vesicant action
and tissue necrosis may result. A doxorubicin liposomal product
(DOXIL) is available for treatment of AIDS-related Kaposi sarcoma
and is given intravenously in a dose of 20 mg/m 2 over 60 minutes
and repeated every 3 weeks. The liposomal formulation also is
approved for ovarian cancer at a dose of 50 mg/m 2 every 4 weeks and
as a treatment for multiple myeloma (in conjunction with bortezomib),
where it is given as a 30-mg/m 2 dose on day 4 of each
21-day cycle. Patients should be advised that the drug may impart a
red color to the urine.
Doxorubicin is effective in malignant lymphomas. In combination
with cyclophosphamide, vinca alkaloids, and other agents, it
is an important ingredient for the successful treatment of lymphomas.
It is a valuable component of various regimens of
chemotherapy for adjuvant and metastatic carcinoma of the breast.
The drug also is particularly beneficial in pediatric and adult sarcomas,
including osteogenic, Ewing, and soft-tissue sarcomas.
Clinical Toxicities. The toxic manifestations of doxorubicin are similar
to those of daunorubicin. Myelosuppression is a major doselimiting
complication, with leukopenia usually reaching a nadir
during the second week of therapy and recovering by the fourth
week; thrombocytopenia and anemia follow a similar pattern but
usually are less pronounced. Stomatitis, mucositis, diarrhea, and
alopecia are common but reversible. Erythematous streaking near
the site of infusion (“ADRIAMYCIN flare”) is a benign local allergic
reaction and should not be confused with extravasation. Facial flushing,
conjunctivitis, and lacrimation may occur rarely. The drug may
produce severe local toxicity in irradiated tissues (e.g., the skin,
heart, lung, esophagus, and GI mucosa) even when the two therapies
are not administered concomitantly.
Cardiomyopathy is the most important long-term toxicity.
Two types of cardiomyopathies may occur:
• An acute form is characterized by abnormal electrocardiographic
changes, including ST- and T-wave alterations and arrhythmias.
This is brief and rarely a serious problem. An acute reversible
reduction in ejection fraction is observed in some patients in the
24 hours after a single dose, and plasma troponin T, a cardiac
enzyme released with myocardial damage, may increase in a
minority of patients in the first few days following drug administration
(Lipshultz et al., 2004). Acute myocardial damage, the
“pericarditis–myocarditis syndrome,” may begin in the days following
drug infusion and is characterized by severe disturbances
in impulse conduction and frank congestive heart failure, often
associated with pericardial effusion.
• Chronic, cumulative dose-related toxicity (usually total doses of
≥550 mg/m 2 ) progress to congestive heart failure. The mortality
rate in patients with congestive failure approaches 50%. Total
doses of doxorubicin as low as 250 mg/m 2 can cause pathological
changes in the myocardium, as demonstrated by subendocardial
biopsies. Nonspecific alterations, including a decrease in the
number of myocardial fibrils, mitochondrial changes, and cellular
degeneration, are visible by electron microscopy. The most
promising noninvasive techniques used to detect the early development
of drug-induced congestive heart failure are radionuclide
cineangiography, which assesses ejection fraction, and