A Textbook of Clinical Pharmacology and Therapeutics

DRUGSUSED INCANCERCHEMOTHERAPY 375

Adverse effects

These include the following:

• 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 methotrexateelimination and
  monitoring plasma methotrexateconcentration 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

Methotrexateabsorption from the gut occurs via a saturable
transport process, large doses being incompletely absorbed. It
is also administered intravenously or intrathecally. After intra-
venous injection, methotrexateplasma concentrations decline
in a triphasic manner, with prolonged terminal elimination
due to enterohepatic circulation. This terminal phase is impor-
tant because toxicity is related to the plasma concentrations
during this phase, as well as to the peak methotrexateconcen-
tration. Alterations in albumin binding affect the pharmacoki-
netics of the drug. Methotrexate penetrates transcellular

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 phar-

macologically inactive but much less soluble than methotrex-

ate, and so contributes to renal toxicity by precipitation and

crystalluria.

Drug interactions

• Probenecid, sulphonamides, salicylates and other NSAIDs
  increase methotrexatetoxicity 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.


• Gentamicinandcisplatinincrease the toxicity of
  methotrexateby 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-Fluorouracilis

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-Fluorouracilis a prodrug that is activated by anabolic phos-

phorylation (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-fluorouracilitself into DNA causes mis-
  matching and faulty mRNA transcripts.

Methotrexate

Dihydrofolate
reductase
Dihydrofolate Tetrahydrofolate

Leucovorin

(folinic acid or

N^5 -formyl tetrahydrofolate)

N5,10-methenylene

tetrahydrofolate

Uridylate

Thymidylate

DNA

Purines

Precursors

N^10 -formyl

tetrahydrofolate

Inhibits

N5,10-methenyl

tetrahydrofolate

Figure 48.5:Folate metabolism: effects of

methotrexate and leucovorin (folinic acid).