Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

MISCELLANEOUS DRUGS
DTIC
Other names
Dacarbazine, imidazole carboxamide, DIC
Clinical applications
The primary indication for DTIC in humans is as a
component of multiagent chemotherapy for malignancies,
including Hodgkin’s lymphoma, melanoma and
soft tissue sarcoma. DTIC is not commonly used in
veterinary medicine. Two reports described its use in
combination with doxorubicin to treat dogs with lymphoma.
Complete responses were observed in some
individuals previously resistant to chemotherapy, suggesting
a potential role in ‘rescue’ therapy. Its use as a
single agent in canine lymphoma has not been evaluated,
nor has its use in cats for any malignancy. Its value
for treating melanoma and soft tissue sarcoma in animals
is not known.
Mechanism of action
Dacarbazine was synthesized as a purine analog but its
antitumor activity remains unknown. It is a cell cyclenonspecific
agent.
Mechanism of drug resistance
Because the mechanism of action is poorly defined, the
mechanisms of resistance remain so also.
Formulations and dose rates
Dacarbazine should be stored at 2–8°C. Once reconstituted, it is
stable for 8 h at room temperature or 72 h at 2–8°C. DTIC in aqueous
solution (10 mg/mL) is stable for 72 h at 4°C in the dark. The solution
readily undergoes photodecomposition if exposed to UV light and
should be protected from daylight.
DOGS
• Intravenous infusion of 200 mg/m 2 q.24 h for 5 consecutive
days is the standard dose regimen
• Reported dose rates vary from 133 to 200 mg/m 2 IV q.24 h for
5 d every 3–4 weeks
• One source recommends up to 250 mg/m 2 IV daily for 5 d every
3–4 weeks
CATS
• No dose rate has been reported for cats
20 mg/kg, clearance of DTIC from plasma is biphasic
with α and β half-lives of 6 and 90 min. By 6 h after
administration, the cumulative urinary excretion of
DTIC is only 20% of the administered dose, suggesting
rapid and extensive metabolism. Urinary excretion of
DTIC and metabolites is thought to be by tubular secretion.
DTIC enters the CNS only to a limited extent: after
10 min the CSF : plasma ratio is 1 : 7. The plasma halflife
was increased in human patients with hepatic and
renal dysfunction. In the dog, dacarbazine is 27%
protein bound.
Adverse effects
● The adverse effects of dacarbazine as a single
agent have not been investigated in the dog. When
combined with doxorubicin, diarrhea, anorexia,
fever, leukopenia and thrombocytopenia have been
reported but cannot be directly attributed to
dacarbazine.
● Pain occurs during IV infusion. This may be reduced
by diluting the drug in 100–200 mL of 5% dextrose
in water and infusing over 30 min rather than
injecting rapidly. Extravasation may cause tissue
damage.
● Severe myelosuppression is uncommon.
● Anorexia, nausea and vomiting, with onset 1–3 h
after administration and duration up to 24 h; these
may be reduced by pre-emptive treatment with antiemetic
medication. In humans, intensity of these
effects decreases with each subsequent daily dose.
Diarrhea is unusual.
● A mild flu-like adverse effect of DTIC observed in
humans has not been reported for companion
animals.
Contraindications and precautions
Dose reduction should be considered in animals with
liver or kidney dysfunction.
Known drug interactions
DTIC precipitates with hydrocortisone sodium succinate
but not hydrocortisone sodium phosphate.
Hydroxycarbamide (hydroxyurea)
Other names
NSC-23605, HU, HUR
Pharmacokinetics
DTIC is a prodrug and, as a result of the action of
microsomal oxidases, is metabolically activated by N-
demethylation to active alkylating metabolites and
formaldehyde. In dogs, after IV administration of
Clinical applications
The principal use of hydroxycarbamide (hydroxyurea)
has been the treatment of myeloproliferative syndromes
in both the dog and the cat. Polycythemia vera, chronic
granulocytic leukemia, essential thrombocythemia and
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