A Textbook of Clinical Pharmacology and Therapeutics

376 CANCER CHEMOTHERAPY

Adverse effects

• Oral ulceration and diarrhoea is an adverse event in
  approximately 20% of patients.


• Bone marrow suppression – megaloblastic anaemia
  usually occurs about 14 days after starting treatment.


• Cerebellar ataxia (2% incidence) is attributed to
  fluorocitrate, a neurotoxic metabolite that inhibits the
  Krebs cycle by lethal synthesis.


• Patients with dihydropyridine dehydrogenase deficiency
  (enzyme activity 5% of normal) have an increased risk of
  severe mucositis/haematologic suppression.

Pharmacokinetics

5-Fluorouracilis given intravenously because it is variably
absorbed from the gut due to high hepatic first-pass metab-
olism. Deactivation occurs primarily in the liver, where it is
reduced to inactive products that are excreted in the urine.
Only 20% is excreted unchanged in the urine.
Capecitabine, an oral prodrug, is de-esterified and deami-
nated to yield high concentrations of 5-deoxy fluorodeoxyuri-
dine (5-dFdU). 5-dFdU is then converted in the liver, peripheral
tissues and tumour to produce 5-FU concentrations that are
about 10% of the 5-dFdU concentrations. Capecitabineis used
to treat breast, lung and colorectal cancer and has the same tox-
icity profile as 5-FU.

PURINE ANTIMETABOLITES

6-MERCAPTOPURINE

Uses

6-Mercaptopurine(6-MP) is a purine antimetabolite. It is effect-
ive as part of combination therapy for acute leukaemias. It
is also an immunosuppressant (Chapter 50). Other purine

antimetabolites that are used clinically include tioguanine,

fludarabine and 2-chlorodeoxyadenosine [cladrabine] (see

Table 48.7).

Mechanism of action

6-MPrequires transformation by intracellular enzymes to 6-

thioguanine which inhibits purine synthesis.

Adverse effects

These include the following:

• bone marrow suppression (macrocytosis, leukopenia and
  thrombocytopenia);


• mucositis;


• nausea, vomiting and diarrhoea with high doses;


• reversible cholestatic jaundice.

Pharma.cokinetics

Only approximately 15% of 6-MPis absorbed when given

orally. Thiopurine-S-methyltransferase (TPMT) catalyses the

S-methylation and deactivation of thiopurines (6-MP,azathio-

prineand6-thioguanine). TPMT is deficient in one in 300

white Europeans. TPMT-deficient individuals are at very high

risk of haematopoietic suppression with standard doses of 6-

MPbecause of the accumulation of thiopurines. Pretreatment

assessment is currently the only pharmacogenetic test in rou-

tine use (Chapter 14). Xanthine oxidase also contributes appre-

ciably to inactivation of thiopurine drugs. Approximately 20%

of an intravenous dose of 6-MPis excreted in the urine within

six hours, thus renal dysfunction enhances toxicity.

Drug interactions

Allopurinolinhibits xanthine oxidase (Chapter 26). The usual

dose of 6-MPshould be reduced by 75% to avoid toxicity in

Uridine phosphorylase

5-FU 5-Fluorouridine

Uridine

kinase

5-Fluorouridylate

Phosphoribosyl
dihydrouracilHepatic transferase
dehydrogenase

Dihydro 5-FU

Catabolism

RNA

DNA

5-Fluorouridine

diphosphate

5-Fluorodeoxyuridylate

Inhibits

Uridine monophosphate

Thymidylate

synthetase

Thymidine monophosphate

Figure 48.6:Metabolism and activation of

5-fluorouracil (5-FU).