Small Animal Clinical Pharmacology - CYF MEDICAL DISTRIBUTION

MISCELLANEOUS DRUGS
binding to dihydrofolate reductase and upregulation of
dihydrofolate reductase activity have been described in
methotrexate-resistant tumors.
Formulations and dose rates
Methotrexate should be stored at room temperature and protected
from light.
DOGS AND CATS
• 0.8 mg/kg or 2.5–5.0 mg/m 2
• Some veterinary oncologists recommend a maximum dose of
15 mg/dog
• Methotrexate is administered as an IV bolus and extravasation
does not cause soft tissue necrosis
• A protocol for high-dose (3–6 g/m 2 ) methotrexate with
leucovorin (a reduced folate) rescue has been used to treat
dogs with osteosarcoma. The treatments were well tolerated
but did not result in prolonged survival
Pharmacokinetics
Methotrexate is absorbed from the intestinal tract by a
saturable transport mechanism. Small doses are well
absorbed. Higher doses are incompletely absorbed.
Methotrexate is loosely bound to albumin. Multiple
drug half-lives occur in the plasma. In humans, the terminal
half-life is 8–27 h. The primary route of methotrexate
elimination is via renal excretion, which occurs
in the first 12 h after administration. There is also
enterohepatic circulation and metabolism of a small
fraction of the drug within the gastrointestinal tract by
intestinal flora. In the liver, methotrexate is converted
to the polyglutamate form, which persists in the liver
for months.
Adverse effects
● Gastrointestinal toxicity limits the clinical
usefulness of methotrexate without leucovorin
rescue in dogs.
● Neutropenia occurs 4–6 d after high-dose
methotrexate treatment but is not common with
low-dose therapy.
● Toxicoses reported in humans and not in
veterinary patients include portal fibrosis, cirrhosis,
pneumonitis and anaphylaxis.
Known drug interactions
● l-asparaginase has been reported to decrease
methotrexate toxicity and antitumor activity in
humans. Demonstration of a protective effect of l-
asparaginase from methotrexate toxicity has been
attempted but has not been successfully shown in
dogs.
● High-dose toxicity to normal tissues can be blocked
by leucovorin.
● Nonsteroidal anti-inflammatory drugs decrease renal
clearance of methotrexate and increase its toxicity.
● In infusions, methotrexate is incompatible with bleomycin,
5-fluorouracil, prednisolone sodium phosphate,
droperidol and ranitidine.
MISCELLANEOUS DRUGS
L-Asparaginase
Other names
Colaspase, l-ASP, crasnitin, asnase, amido hydrolase, NSC-
109229 (E. coli), NSC-106997 (Erwinia),
Crisantaspase/Erwinase
Clinical applications
The veterinary use of l-asparaginase has been in multidrug
protocols for both canine and feline lymphoma. Its
use in acute lymphoid leukemia and mast cell tumors
has been proposed.
Mechanism of action
One approach to cancer therapy is to identify the differences
between tumor cells and normal cells and to
exploit those differences therapeutically. Although this
is a rational approach, it has been difficult to identify
consistent differences between the two types of cell and
the only drug resulting from this approach has been l-
asparaginase. l-Asparaginase is a cell cycle-specific
drug, which exerts its activity in the G 1 phase of the cell
cycle.
Normal cells can synthesize l-asparagine from glutamine
and l-aspartic acid, but some tumor cells lack l-
asparagine synthetase, the catalyst for l-asparagine
production. The conversion of l-asparagine to aspartic
acid and ammonia by l-asparaginase starves the tumor
cells of l-asparagine. Depletion of l-asparagine inhibits
protein synthesis and results in cytotoxicity. The most
commonly used l-asparaginase formulation is purified
from Escherichia coli. However, enzyme derived from
Erwinia carotovora is also available.
Mechanism of drug resistance
Resistance to treatment with l-asparaginase arises
from selection of a tumor cell population containing l-
asparagine synthetase or a derepression of the synthetase
as a result of a fall in intracellular l-asparagine
levels. The patient’s immune system also contributes to
l-asparaginase resistance by producing antibodies with
the capability to accelerate enzyme clearance and reduce
therapeutic effectiveness.
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