Medline ® Abstract for Reference 24
Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene.
Maring JG, van Kuilenburg AB, Haasjes J, Piersma H, Groen HJ, Uges DR, Van Gennip AH, De Vries EG
Br J Cancer. 2002;86(7):1028.
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.
Department of Pharmacy, Diaconessen Hospital, Meppel and Bethesda Hospital, Hoogeveen, Hoogeveenseweg 38, 7943 KA Meppel, The Netherlands. email@example.com