C H A P T E R 1 4
Antineoplastic agents
203
Pharmacokinetics
Methotrexate is absorbed well from the GI tract and
is excreted unchanged in the urine. People with renal
impairment may require reduced dose and increased
monitoring when taking methotrexate. Methotrexate
readily crosses the blood–brain barrier. Cytarabine,
clofarabine, colaspase, fluorouracil, gemcitabine and
pemetrexed are not absorbed well from the GI tract and
need to be administered parenterally. They are metabo
lised in the liver and excreted in the urine, necessitating
close monitoring of individuals with hepatic or renal
impairment who are receiving these drugs. Mercapto
purine and thioguanine are absorbed slowly from the
GI tract and are metabolised in the liver and excreted
in the urine.
Contraindications and cautions
Antimetabolites are contraindicated for use during
pregnancy and breastfeeding
because of the potential
for severe effects on the fetus and neonate
. Caution is
necessary when administering antimetabolites to any
individual with a known allergy to any of them; with
bone marrow suppression,
which is often the index for
redosing and dosing levels
; with renal or hepatic dys
function,
which might interfere with the metabolism
or excretion of these drugs and often indicates a need
to change the dose
; and with known GI ulcerations or
ulcerative diseases
that might be exacerbated by the
effects of these drugs.
Adverse effects
Adverse effects frequently encountered with the use of
the antimetabolites are listed here. To counteract the
effects of treatment with one antimetabolite—metho
trexate—the drug Leucovorin is sometimes given (see
Box 14.6).
Haematological effects include bone marrow sup
pression, with leucopenia, thrombocytopenia, anaemia
and pancytopenia, secondary to the effects of the drugs
on the rapidly multiplying cells of the bone marrow.
Toxic GI effects include nausea, vomiting, anorexia,
diarrhoea and mucous membrane deterioration, all of
which are related to drug effects on the rapidly multiply
ing cells of the GI tract. CNS effects include headache,
drowsiness, aphasia, fatigue, malaise and dizziness.
People should be advised to take precautions if these
conditions occur. There is a risk of pulmonary toxicity,
including interstitial pneumonitis with these drugs. As
with alkylating agents, effects of the antimetabolites
may include possible hepatic or renal toxicity, depending
on the exact mechanism of action. Alopecia may also
occur.
Clinically important drug–drug interactions
Antimetabolites that are known to cause hepatic or
renal toxicity should be used with care with any other
drugs known to have the same effect. In addition, drugs
that are toxic to the liver may adversely affect drugs
that are metabolised in the liver or that act in the liver
(e.g. oral anticoagulants). Check for specific drug–drug
interactions for each agent in a drug guide.
Leucovorin (calcium folinate) is an active form of folic
acid that is used to “rescue” normal cells from the
adverse effects of methotrexate therapy in the treatment
of osteosarcoma. This drug is also used to treat folic
acid deficiency conditions such as sprue, nutritional
deficiency, pregnancy and breastfeeding. Leucovorin is
given orally or intravenously at the time of methotrexate
therapy and for the next 72 hours at a dose of 12 to
15 g/m
2
PO or IV followed by 10 mg/m
2
PO q 6 hours
for 72 hours. Use of this drug has been associated with
pain at the injection site.
■■
BOX 14.6
A drug that protects against an
antimetabolite
Prototype summary: Methotrexate
Indications:
Treatment of gestational
choriocarcinoma, chorioadenoma destruens,
hydatidiform, meningeal leukaemia; symptomatic
control of severe psoriasis; rheumatoid arthritis;
juvenile rheumatoid arthritis.
Actions:
Inhibits folic acid reductase, leading
to inhibition of DNA synthesis and inhibition
of cellular replication; affects the most rapidly
dividing cells.
Pharmacokinetics:
Route
Onset
Peak
Oral
Varies
1–4 hours
Intravenous
Rapid
0.5–2 hours
T
1/2
:
2–4 hours, excreted unchanged in the urine.
Adverse effects:
Fatigue, malaise, rashes, alopecia,
ulcerative stomatitis, hepatic toxicity, severe bone
marrow suppression, interstitial pneumonitis, chills,
fever, anaphylaxis.
