Pharmacokinetics of orally administered uracil in healthy volunteers and in DPD-deficient patients, a possible tool for screening of DPD deficiencyReport as inadecuate




Pharmacokinetics of orally administered uracil in healthy volunteers and in DPD-deficient patients, a possible tool for screening of DPD deficiency - Download this document for free, or read online. Document in PDF available to download.

Cancer Chemotherapy and Pharmacology

, Volume 68, Issue 6, pp 1611–1617

First Online: 18 May 2011Received: 08 February 2011Accepted: 16 April 2011

Abstract

PurposeDihydropyrimidine dehydrogenase DPD deficiency can lead to severe toxicity in patients treated with standard doses of 5-fluorouracil 5-FU. Oral uracil administration and subsequent measurement of uracil and dihydrouracil DHU plasma concentrations might detect patients with DPD deficiency. This study compares the pharmacokinetics of uracil and DHU after oral uracil administration in subjects with normal and deficient DPD status.

MethodsFive hundred milligrams of uracil per metre square was administered orally to 11 subjects with normal DPD status and to 10 subjects with reduced DPD activity. Repeated administration n = 3 of this dose was performed in 4 subjects, and 1,000 mg uracil-m was administered to 4 subjects to assess intra-individual variation and linearity of pharmacokinetics.

ResultsIn subjects with normal DPD status, 500 mg-m uracil resulted in uracil Cmax levels of 14.4 ± 4.7 mg-L at Tmax = 30.0 ± 11.6 min, and in DPD-deficient subjects, 20.0 ± 4.5 mg-L at 31.5 ± 1.1 min. The uracil AUC0>180 was 31.2 ± 5.1 mg L-h in DPD-deficient subjects, which was significantly higher P < 0.05 than in the subjects with normal DPD status 13.8 ± 3.9 mg L-h. Repeated uracil dosing showed reproducible uracil PK in subjects with normal DPD status, and dose elevation of uracil suggested linear pharmacokinetics.

ConclusionThe pharmacokinetics of uracil differs significantly between subjects with a normal DPD activity and those with a deficient DPD status. The AUC and Cmax of uracil can be useful as a diagnostic tool to differentiate patients with regard to DPD status.

KeywordsDihydropyrimide dehydrogenase Uracil Cancer 5-fluorouracil Pharmacokinetics A part of the data were presented at ASCO 2004 by J. G. Maring.

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Author: Maurice C. van Staveren - Barbara Theeuwes-Oonk - Henk Jan Guchelaar - André B. P. van Kuilenburg - Jan Gerard Maring

Source: https://link.springer.com/







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