Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene

Abstract

5-fluorouracil pharmacokinetics, dihydropyrimidine dehydrogenase-activity and DNA sequence analysis were compared between a patient with extreme 5-fluorouracil induced toxicity and six control patients with normal 5-fluorouracil related symptoms. Patients were treated for colorectal cancer and received chemotherapy consisting of leucovorin 20 mg m-2 plus 5-fluorouracil 425 mg m-2. Blood sampling was carried out on day 1 of the first cycle. The 5-fluorouracil area under the curve0→3h in the index patient was 24.1 mg h l-1 compared to 9.8 ± 3.6 (range 5.4-15.3) mg h l-1 in control patients. The 5-fluorouracil clearance was 520 ml min-1 vs 1293±302 (range 980-1780) ml min-1 in controls. The activity of dihydropyrimidine dehydrogenase in mononuclear cells was lower in the index patient (5.5 nmol mg h-1) compared to the six controls (10.3±1.6, range 8.0-11.7 nmol mg h-1). Sequence analysis of the dihydropyrimidine dehydrogenase gene revealed that the index patient was heterozygous for a IVSI4+IG>A point mutation. Our results indicate that the inactivation of one dihydropyrimidine dehydrogenase allele can result in a strong reduction in 5-fluorouracil clearance, causing severe 5-fluorouracil induced toxicity. © 2002 Cancer Research UK.