Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

CHAPTER 15 CANCER CHEMOTHERAPY
best-fit plasma level time area under the curve was
4024 g/mLxmin.
A proposed model of pharmacokinetics included
flow-dependent clearance of 5-fluorouracil by the liver
and linear elimination via the kidney. Total plasma
clearance of 5-fluorouracil exceeds cardiac output and,
consequently, extrahepatic pathways of disposition
must be present to account for this phenomenon.
Dose-dependent pulmonary extraction and clearance
of 5-flourouracil has been demonstrated in the dog.
As the dose of 5-fluorouracil increases, the percentage
of drug cleared by the lung decreases. 5-Fluorouracil
enters CSF and attains concentrations similar to plasma
levels.
Adverse effects
● Some of the best information on 5-fluorouracil toxicity
comes from cases of accidental ingestion in dogs.
Accidental ingestion of 5-fluorouracil occurs in dogs
exposed to their owner’s topical 5-fluorouracil preparation.
Exposure to more than 43 mg/kg resulted in
death in all dogs exposed. Clinical signs of toxicosis
occurred within 1 h of ingestion and included seizures,
vomiting, tremors, respiratory distress, hypersalivation,
diarrhea, depression, ataxia and cardiac
arrhythmias.
● Temporary hair loss may occur in dogs receiving a
nonlethal dose of 5-fluorouracil.
● Similar clinical signs as described above may occur
when topical 5-fluorouracil is applied to dogs for the
treatment of skin tumors.
Known drug interactions
Concurrent administration of cimetidine or α-interferon
may decrease 5-fluorouracil clearance.
Gemcitabine
Other names
Gemzar, 2′- 2′-difluorodeoxycytidine, dFdC
Clinical applications
Only limited clinical response has been observed in dogs
with lymphoma, oral melanoma, hepatocellular carcinoma
and perianal squamous cell carcinoma.
Mechanism of action
Gemcitabine is a difluorinated pyrimidine analog of
deoxycytidine. Once the drug enters the cell via facilitated
nucleoside transport, it is metabolized to the active
nucleoside form. During DNA synthesis the active
metabolites are incorporated into the DNA molecule
and ultimately block subsequent DNA replication.
Formulations and dose rates
DOGS
• 675 mg/m 2 IV q.2 weeks diluted in 10 mL/kg 0.9% NaCl and
given over 30 min
CATS
• 250 mg/m 2 IV (preliminary information)
Pharmacokinetics
Dogs metabolize gemcitabine by a two-compartment
model. The drug is deaminated and cleared through the
kidneys. There is minimal protein binding. Half-life is
1.38 h. Approximately 76–86% of the dose is detected
as metabolites in the urine 24 h after administration.
Adverse effects
● Rare and mild hematological toxicity.
● Mild gastrointestinal toxicity.
Known drug interactions
Use of low-dose (25–50 mg/m 2 ) gemcitabine twice
weekly as a radiation sensitizer resulted in unacceptable
hematological and local tissue toxicity.
Methotrexate
Other names
NSC-740, amethopterin, sodium methotrexate
Clinical applications
Methotrexate is a component of multidrug protocols for
the treatment of canine and feline lymphoma and some
soft tissue sarcomas. Its efficacy as a single agent in these
neoplasms has not been demonstrated. It has also been
used in the management of sclerosing cholangitis in
cats.
Mechanism of action
Inhibition of dihydrofolate reductase by methotrexate
leads to depletion of reduced folates, which are necessary
for DNA synthesis. Polyglutamates of methotrexate
and dihydrofolate inhibit both purine and thymidylate
biosynthesis. Leucovorin is a reduced folate that has
been used to rescue patients from methotrexate
toxicity.
Mechanism of drug resistance
Multiple metabolic steps lead to methotrexate-induced
cytotoxicity. Derangement in all phases of methotrexate
transport and metabolism contribute to metho -
trexate resistance. Decreased transmembrane transport,
decreased formation of polyglutamates, decreased
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