1. ¹Department of Pharmacy, Diaconessen Hospital, Meppel and Bethesda Hospital, Hoogeveen, Hoogeveenseweg 38, 7943 KA Meppel, The Netherlands
2. ²Department of Clinical Chemistry, Academic Medical Center and Emma Children's Hospital, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
3. ³Department of Internal Medicine, Martini Hospital, Van Swietenlaan 4, 9728 NZ Groningen, The Netherlands
4. ⁴Department of Pulmonary Medicine, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
5. ⁵Department of Pharmacy, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands
6. ⁶Department of Medical Oncology, University Hospital, Hanzeplein 1, 9713 GZ Groningen, The Netherlands

Correspondence: J G Maring, Department of Pharmacy, Diaconessen Hospital, PO Box 502, 7940 AM Meppel, The Netherlands. E-mail: maring@diacmeppel.nl

Received 6 July 2001; Revised 31 December 2001; Accepted 22 January 2002.

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 9.83.6 (range 5.4–15.3) mg h l^-1 in control patients. The 5-fluorouracil clearance was 520 ml min^-1 vs 1293302 (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 (10.31.6, 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.