A Textbook of Clinical Pharmacology and Therapeutics

Adverse effects
Methotrexate
Inhibits
Dihydrofolate
reductase
Dihydrofolate Tetrahydrofolate
Leucovorin
(folinic acid or
N 5 -formyl tetrahydrofolate)
These include the following:
N 10 -formyl
tetrahydrofolate
N 5,10 -methenyl
tetrahydrofolate
N 5,10 -methenylene
tetrahydrofolate
• myelosuppression;
• nausea and vomiting;
• stomatitis;
• diarrhoea;
• cirrhosis – chronic low-dose administration (as for
psoriasis) can cause chronic active hepatitis and cirrhosis,
interstitial pneumonitis and osteoporosis;
• renal dysfunction and acute vasculitis (after high-dose
treatment);
• intrathecal administration also causes special problems,
including convulsions, and chemical arachnoiditis leading
to paraplegia, cerebellar dysfunction and cranial nerve
palsies and a chronic demyelinating encephalitis.
Renal insufficiency reduces methotrexate elimination and
monitoring plasma methotrexate concentration is essential
under these circumstances. Acute renal failure can be caused
by tubular obstruction with crystals of methotrexate. Diuresis
(�3 L/day) with alkalinization (pH �7 ) of the urine using
intravenous sodium bicarbonate reduces nephrotoxicity.
Renal damage is caused by the precipitation of methotrexate
and 7-hydroxymethotrexate in the tubules, and these weak
acids are more water soluble at an alkaline pH, which favours
their charged form (Chapter 6).
Pharmacokinetics
Methotrexate absorption from the gut occurs via a saturable
transport process, large doses being incompletely absorbed. It
is also administered intravenously or intrathecally. After intravenous
injection, methotrexate plasma concentrations decline
in a triphasic manner, with prolonged terminal elimination
due to enterohepatic circulation. This terminal phase is important
because toxicity is related to the plasma concentrations
during this phase, as well as to the peak methotrexate concentration.
Alterations in albumin binding affect the pharmacokinetics
of the drug. Methotrexate penetrates transcellular
Precursors
Purines
DNA
Thymidylate
Uridylate
DRUGS USED IN CANCER CHEMOTHERAPY 375
Figure 48.5: Folate metabolism: effects of
methotrexate and leucovorin (folinic acid).
water (e.g. the plasma: CSF ratio is approximately 30:1) slowly
by passive diffusion. About 80–95% of a dose of methotrexate
is renally excreted (by filtration and active tubular secretion)
as unchanged drug or metabolites. It is partly metabolized
by the gut flora during enterohepatic circulation.
7-Hydroxymethotrexate is produced in the liver and is pharmacologically
inactive but much less soluble than methotrexate,
and so contributes to renal toxicity by precipitation and
crystalluria.
Drug interactions
• Probenecid, sulphonamides, salicylates and other NSAIDs
increase methotrexate toxicity by competing for renal
tubular secretion, while simultaneously displacing it from
plasma albumin. Other weak acids including furosemide
and high-dose vitamin C compete for renal secretion.
• Gentamicin and cisplatin increase the toxicity of
methotrexate by compromising renal excretion.
PYRIMIDINE ANTIMETABOLITES
5-FLUOROURACIL
Uses
5-Fluorouracil (5-FU) is used to treat solid tumours of the
breast, ovary, oesophagus, colon and skin. 5-Fluorouracil is
administered by intravenous injection. Dose reduction is
required for hepatic dysfunction or in patients with a genetic
deficiency of dihydropyridine dehydrogenase.
Mechanism of action
5-Fluorouracil is a prodrug that is activated by anabolic phosphorylation
(Figure 48.6) to form:
• 5-fluorouridine monophosphate, which is incorporated
into RNA, inhibiting its function and its polyadenylation;
• 5-fluorodeoxyuridylate, which binds strongly to
thymidylate synthetase and inhibits DNA synthesis.
Incorporation of 5-fluorouracil itself into DNA causes mismatching
and faulty mRNA transcripts.