Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

ALKYLATING AGENTS
Pharmacokinetics
BCNU is a nitrosourea alkylating agent. It is relatively
nonionized and lipid soluble and crosses the blood–
brain barrier quite effectively. Intravenously administered
BCNU is rapidly degraded to reactive intermediates
with a half-life of approximately 15 min in humans. In
studies on dogs, using radiolabeled BCNU, approximately
28–30% of the total radioactivity administered
was excreted in the urine in 6 h.
Adverse effects
● Myelosuppression is dose limiting, with neutrophil
nadir at 7–9 d and recovery delayed for 15 d, and
was pronounced when BCNU was used in a multiagent
protocol (vincristine, BCNU and prednisone)
for lymphoma. Thrombocytopenia is also likely. In
humans, bone marrow toxicity is cumulative and
dose adjustments are considered on the basis of nadir
counts from the prior dose.
● Pulmonary fibrosis was reported in one dog given
eight doses of BCNU and is a common adverse effect
related to cumulative dose in humans.
● Nausea and vomiting are common, dose-related
effects in humans; hepatic and other toxicities are
uncommon.
● Rapid administration may cause intense pain and
burning sensation at the injection site.
Contraindications and precautions
BCNU should be used with caution in myelosuppressed
patients.
Known drug interactions
As with other cytotoxic agents, the myelosuppressive
effects of BCNU may be enhanced by other myelosuppressive
drugs.
Busulfan
Clinical applications
Busulfan is an alkyl alkane sulfonate alkylating agent.
It is selectively cytotoxic to myeloid cells, leaving lymphoid
cells relatively undamaged. Busulfan is principally
indicated for the treatment of canine chronic granulocytic
leukemia. Its use against this disease in cats is said
to be less successful. It may also be useful to treat polycythemia
vera.
Formulations and dose rates
DOGS AND CATS
• 2–6 mg/m 2 PO q.24 h until the WBC count approaches the
upper limit of the normal range, then either discontinue the
medication or reduce the daily dose to maintain the count at or
just below this level. In humans, the recommended maximum
daily dose is 4 mg
• The blood count should be monitored weekly during induction
of remission; if response is inadequate after 3 weeks, consider
increasing the dose rate
• In humans, if maintenance therapy is required, a dose between
0.5 and 2 mg daily is usual, although much lower doses are
adequate for some individuals
Pharmacokinetics
Busulfan is readily absorbed after oral administration.
In rats, it is extensively metabolized, principally in the
liver, and metabolites are excreted in urine.
Adverse effects
● Myelosuppression (particularly neutropenia and
thrombocytopenia) is the most important toxicity. In
humans, WBC counts may not start to fall until 2
weeks after beginning therapy and may continue to
fall for 2 weeks after the last drug dose. Marrow
recovery may not occur for 3–6 weeks after discontinuing
therapy.
● Nausea and vomiting are unusual in humans.
● Suppression of gonad function occurs in males and
females.
● Other uncommon adverse effects usually reported
after prolonged therapy in humans include skin pigmentation,
pulmonary fibrosis, adrenal insufficiency,
ovarian suppression and secondary neoplasia.
Contraindications and precautions
Busulfan is contraindicated in patients with thrombocytopenia,
neutropenia or pulmonary fibrosis.
Known drug interactions
Busulfan may exacerbate the pulmonary toxicity of
other cytotoxic agents or radiation therapy.
CCNU
Other names
Lomustine
Clinical applications
CCNU is used in the treatment of human brain tumors,
melanoma and as secondary therapy for lymphoma. The
use of CCNU has recently been reported as a single
agent for treating canine mast cell tumors, canine and
feline lymphoma and possibly canine brain tumors.
CCNU may also have efficacy against some sarcomas.
Its exact role in these diseases has yet to be completely
clarified but it will probably find utility as one component
of a multidrug treatment regimen.
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