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

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 curve(0→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 IVS14+1G>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. British Journal of Cancer (2002) 86, 1028–1033. DOI: 10.1038/sj/bjc/6600199 www.bjcancer.com © 2002 Cancer Research UK