Tutorial 5 - Fluoropyrimidines

Question 1

What are fluoropyrimidine drugs?

Answer 1

Antimetabolite/anticancer drugs

Used in the treatment of solid tumours inn breast and colorectal cancer, basal cell carcinomas etc

Question 2

Name some examples of fluoropyrimidine drugs and explain how they are related to each other

Answer 2

5-FU is an active drug

Capecitabine and Tegafur are pro-drug forms of 5-FU

Question 3

Why is 5-FU often administered as a prodrug?

Answer 3

Conjugating it with other molecules to form a pro drug slows the metabolism, to try an prevent accumulation of toxic 5-FU
Also prodrugs can be taken orally rather than through IV

Question 4

Describe the mechanism of action of 5-FU

Answer 4

Metabolised into FUTP, which is incorporated into RNA
Metabolised into FdUMP, which inhibits thymidylate synthase, preventing pyrimidine synthesis
FdUMP metabolised further into FdUTP, which is incorporated into DNA

Question 5

Describe the detoxification of 5-FU

Answer 5

80% of 5-FU is metabolised into inactive metabolites by DPD, and excreted in the urine

Question 6

What are the side effects of fluoropyrimidine drugs?

Answer 6

GI symptoms
Neutropenic fever
Anaemia 
Thrombocytopenia
Redness/swelling of the hands and feet

Question 7

How can genetic variation affect the pharmacokinetics of fluoropyrimidine drugs?

Answer 7

Variants in the DYPD gene may lead to reduced DPD activity. Increases risk of severe side effects, neurotoxicity and bone marrow suppression. Can be fatal.

Question 8

How can genetic variation affect the pharmacodynamics of fluoropyrimidine drugs?

Answer 8

Variants in the TYMS gene may lead to variable activity of thymidylate synthase. Can increase risk of drug toxicity and reduce efficacy of fluoropyrimidines.