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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)

Bottom Line: 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 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Diaconessen Hospital, Meppel and Bethesda Hospital, Hoogeveen, Hoogeveenseweg 38, 7943 KA Meppel, The Netherlands. maring@diacmeppel.nl

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.

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Pharmacokinetics of 5-FU. Shown are 5-FU plasma levels observed in a patient with a IVS14+1G>A mutation in the DPYD gene (solid diamond) and the 5-FU plasma levels resulting from simulation of a normal renal function in the same patient. 5-FU plasma levels from control patients are depicted as mean±s.d. (solid triangle; n=6).
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fig2: Pharmacokinetics of 5-FU. Shown are 5-FU plasma levels observed in a patient with a IVS14+1G>A mutation in the DPYD gene (solid diamond) and the 5-FU plasma levels resulting from simulation of a normal renal function in the same patient. 5-FU plasma levels from control patients are depicted as mean±s.d. (solid triangle; n=6).

Mentions: The clearance of 5-FU was considerable slower in the index patient than in the six control patients. In all control patients the plasma level at t=90 min was below 0.1 mg l−1, whereas in the index patient the plasma level was still 3.8 mg l−1 at this time point (see Figure 2Figure 2


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)

Pharmacokinetics of 5-FU. Shown are 5-FU plasma levels observed in a patient with a IVS14+1G>A mutation in the DPYD gene (solid diamond) and the 5-FU plasma levels resulting from simulation of a normal renal function in the same patient. 5-FU plasma levels from control patients are depicted as mean±s.d. (solid triangle; n=6).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2364178&req=5

fig2: Pharmacokinetics of 5-FU. Shown are 5-FU plasma levels observed in a patient with a IVS14+1G>A mutation in the DPYD gene (solid diamond) and the 5-FU plasma levels resulting from simulation of a normal renal function in the same patient. 5-FU plasma levels from control patients are depicted as mean±s.d. (solid triangle; n=6).
Mentions: The clearance of 5-FU was considerable slower in the index patient than in the six control patients. In all control patients the plasma level at t=90 min was below 0.1 mg l−1, whereas in the index patient the plasma level was still 3.8 mg l−1 at this time point (see Figure 2Figure 2

Bottom Line: 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 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)).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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Diaconessen Hospital, Meppel and Bethesda Hospital, Hoogeveen, Hoogeveenseweg 38, 7943 KA Meppel, The Netherlands. maring@diacmeppel.nl

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.

Show MeSH
Related in: MedlinePlus