Pharmacokinetic Test Dose to Detect Risk for Excessive Toxicity Prior to 5-Fluorouracil Therapy

 

Primary metabolite for 5-FU: 5-fluor-5,6-dihydrouracil (5-FDHU)

 

Metabolic system: dihydropyrimidine dehydrogenase (DPD)

 

Patients who are deficient in DPD will be slow metabolizers of 5-FU and are more likely to experience serious toxicity. Slow metabolism does not explain all cases of severe toxicity but does identify an important group.

 

Protocol: test dose 5-FU 250 mg per square meter body surface area

 

Pharmacokinetic parameters determined:

(1) half-life (beta phase) 5-FU in hours

(2) total body clearance of 5-FU in liters per hour per square meter

(3) time to 5-FDHU peak concentration in minutes

Parameter	Normal	Slow Metabolizers
5-FU half-life (beta)	0.16 +/- 0.15 hours	> 5 hours
total body clearance	65.7 +/- 32 L per h per sq m	< 1 liter per h per sq m
time to peak 5-FDHU	27 +/- 10 minutes	>= 45 minutes

 

A patient suspected of slow metabolism was treated with irinotecan instead.

 

An assay for DPD activity in peripheral blood mononuclear cells can be performed but is difficult to perform reliably and may not be readily available.