title: 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 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.
authors.affiliation: Department of Pharmacy, Diaconessen Hospital, Meppel and Bethesda Hospital, Hoogeveen, Hoogeveenseweg 38, 7943 KA Meppel, The Netherlands. maring@diacmeppel.nl
authors.forename: J G
authors.initials: JG
authors.lastname: Maring
authors.forename: A B P
authors.initials: AB
authors.lastname: van Kuilenburg
authors.forename: J
authors.initials: J
authors.lastname: Haasjes
authors.forename: H
authors.initials: H
authors.lastname: Piersma
authors.forename: H J M
authors.initials: HJ
authors.lastname: Groen
authors.forename: D R A
authors.initials: DR
authors.lastname: Uges
authors.forename: A H
authors.initials: AH
authors.lastname: Van Gennip
authors.forename: E G E
authors.initials: EG
authors.lastname: De Vries
mesh_terms: D000368:Aged; D000483:Alleles; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000188:drug therapy; D004273:DNA, Neoplasm / Q000235:genetics*; D042943:Dihydrouracil Dehydrogenase (NADP); D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000493:pharmacokinetics*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D010088:Oxidoreductases / Q000235:genetics / Q000494:pharmacology*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D010088:Oxidoreductases; D042943:Dihydrouracil Dehydrogenase (NADP); D002955:Leucovorin; D005472:Fluorouracil