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

1686 fall for >1 month after discontinuing the drug, it is recommended
that busulfan be withdrawn when the total leukocyte count has
declined to ~15,000 cells/mm 3 . A normal leukocyte count usually is
achieved within 12-20 weeks. During remission, daily treatment
resumes when the total leukocyte count reaches ~50,000 cells/mm 3 .
Daily maintenance doses are 1-3 mg. In high-dose therapy, doses of
1 mg/kg are given every 6 hours for 4 days, with adjustment based
on pharmacokinetics.
In high-dose regimens, busulfan is given at 0.8 mg/kg every
6 hours for 4 days. Anticonvulsants must be used concomitantly to
protect against acute CNS toxicities, including tonic-clonic seizures,
which may occur several hours after each dose. Busulfan induces
the metabolism of phenytoin. In patients requiring anti-seizure medication,
non-enzyme-inducing drugs such as lorazepam are recommended
as an alternative to phenytoin. When phenytoin is used
concurrently, plasma busulfan levels should be monitored and the
busulfan dose adjusted accordingly.
Clinical Toxicity. The major toxic effects of busulfan are related to
its myelosuppressive properties, and prolonged thrombocytopenia
may be a hazard. Occasionally, patients experience nausea, vomiting,
and diarrhea. Long-term use leads to impotence, sterility, amenorrhea,
and fetal malformation. Rarely, patients develop asthenia and
hypotension, a syndrome resembling Addison’s disease, but without
abnormalities of corticosteroid production.
High-dose busulfan causes VOD of the liver in ≤10% of
patients, as well as seizures, hemorrhagic cystitis, permanent alopecia,
and cataracts. The coincidence of VOD and hepatotoxicity is increased
by its co-administration with drugs that inhibit CYPs, including imidazoles
and metronidazole, possibly through inhibition of the clearance
of busulfan and/or its toxic metabolites (Nilsson et al., 2003).
SECTION VIII
CHEMOTHERAPY OF NEOPLASTIC DISEASES
Nitrosoureas
The nitrosoureas have an important role in the treatment
of brain tumors and find occasional use in treating lymphomas
and in high-dose regimens with bone marrow
reconstitution. They function as bifunctional alkylating
agents but differ from conventional nitrogen mustards
in both pharmacological and toxicological properties.
Carmustine (BCNU) and lomustine (CCNU) are highly
lipophilic and thus readily cross the blood-brain barrier, an important
property in the treatment of brain tumors. Unfortunately, with the
exception of streptozocin, nitrosoureas cause profound and delayed
myelosuppression with recovery 4-6 weeks after a single dose.
Long-term treatment with the nitrosoureas, especially semustine
(methyl-CCNU), has resulted in renal failure. As with other alkylating
agents, the nitrosoureas are highly carcinogenic and mutagenic.
They generate both alkylating and carbamylating moieties as illustrated
in Figure 61–4.
Carmustine (BCNU). Carmustine’s major action is its
alkylation of DNA at the O 6 -guanine position, an
adduct repaired by MGMT. Methylation of the MGMT
promoter inhibits its expression in ~30% of primary
gliomas and is associated with sensitivity to
nitrosoureas. In high doses with bone marrow rescue, it
produces hepatic VOD, pulmonary fibrosis, renal failure,
and secondary leukemia (Tew et al., 2001).
Absorption, Fate, and Excretion. Carmustine is unstable in aqueous
solution and in body fluids. After intravenous infusion, it disappears
from the plasma with a highly variable t 1/2
of ≥15-90
minutes. Approximately 30-80% of the drug appears in the urine
within 24 hours as degradation products. The alkylating metabolites
enter rapidly into the cerebrospinal fluid (CSF), and their
concentrations in the CSF reach 15-30% of the concurrent plasma
values.
Therapeutic Uses. When used alone, carmustine (BICNU) is administered
intravenously at doses of 150-200 mg/m 2 , given by infusion
over 1-2 hours and repeated every 6 weeks.
Because of its ability to cross the blood-brain barrier, carmustine
has been used in the treatment of malignant gliomas but
has been increasingly replaced by temozolomide. An implantable
carmustine wafer (GLIADEL) is available for use as an adjunct to
surgery and radiation in newly diagnosed high-grade malignant
glioma patients and as an adjunct to surgery for recurrent glioblastoma
multiforme.
Streptozocin. This antibiotic has a methylnitrosourea
(MNU) moiety attached to the 2-carbon of glucose. It
has a high affinity for cells of the islets of Langerhans
and causes diabetes in experimental animals.
Absorption, Fate, and Excretion. Streptozocin is rapidly degraded following
intravenous administration. The t 1/2
of the drug is ~15 minutes.
Only 10-20% of a dose is recovered intact in the urine.
Therapeutic Uses. Streptozocin (ZANOSAR) is used exclusively in the
treatment of human pancreatic islet cell carcinoma and malignant
carcinoid tumors. It is administered intravenously, 500 mg/m 2 once
daily for 5 days; this course is repeated every 6 weeks. Alternatively,
1000 mg/m 2 can be given weekly for 2 weeks, and the weekly dose
then can be increased to a maximum of 1500 mg/m 2 , depending on
tolerance and response.
Clinical Toxicity. Nausea is frequent. Mild, reversible renal or
hepatic toxicity occurs in approximately two-thirds of cases; in
<10% of patients, renal toxicity may be cumulative with each dose
and may lead to irreversible renal failure. Proteinuria is an early
sign of tubular damage and impending renal failure. Streptozocin
should not be given with other nephrotoxic drugs. Hematological
toxicity—anemia, leukopenia, or thrombocytopenia—occurs in
20% of patients.
Triazenes
Dacarbazine (DTIC). Dacarbazine functions as a methylating
agent after metabolic activation to the
monomethyl triazeno metabolite, MTIC. It kills cells
in all phases of the cell cycle. Resistance has been
ascribed to the removal of methyl groups from the O 6 -
guanine bases in DNA by MGMT.
Absorption, Fate, and Excretion. Dacarbazine is administered intravenously.
After an initial rapid phase of disappearance (t 1/2
of ~20
minutes), dacarbazine is cleared from plasma with a terminal t 1/2
of
~5 hours. The t 1/2
is prolonged in the presence of hepatic or renal