PT  - JOURNAL ARTICLE
AU  - D H Ho
AU  - W P Covington
AU  - R Pazdur
AU  - N S Brown
AU  - J Kuritani
AU  - R A Newman
AU  - M N Raber
AU  - I H Krakoff
TI  - Clinical pharmacology of combined oral uracil and ftorafur.
DP  - 1992 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 936--940
VI  - 20
IP  - 6
4099  - http://dmd.aspetjournals.org/content/20/6/936.short
4100  - http://dmd.aspetjournals.org/content/20/6/936.full
SO  - Drug Metab Dispos1992 Nov 01; 20
AB  - Phase I clinical trials of the combination of oral uracil with ftorafur (Ft) were conducted in patients with solid tumors over either a 5-day (345 mg/m2/day) or a 28-day (160 mg/m2/day) period. The uracil dose, which was four times the Ft dose (molar basis), was previously shown to be optimal at inhibiting the degradation of 5-fluorouracil (5-FU). Pharmacology was performed on the first dose of the first day of therapy. Ft was measured by HPLC, whereas uracil and 5-FU were measured using GC/MS. Plasma levels were highest for Ft, followed by uracil and 5-FU at all time points. Peak and trough levels after selected subsequent doses were also measured; these varied in the individual from day to day. Maximum plasma levels (Cpmax) for Ft, uracil, and 5-FU except in one patient were achieved at 0.6-2.1 hr, 0.6-4.1 hr, and 0.7-2.0 hr, respectively. Generally, lower doses yielded more rapid decay of 5-FU and uracil levels than did higher doses. No correlation was observed between myelotoxicities (granulocytopenia and leukopenia) and the Cpmax and AUC0-6hr of Ft (p > 0.2). However, after the highest uracil and Ft dose (approximately 300 mg/m2/Ft study dose), the Cpmax and AUC0-6hr values of 5-FU revealed significant differences (p < 0.05) in three patients each with and without myelotoxicity. These associations were similarly observed with uracil. Our findings thus indicate that measuring plasma uracil and more importantly, the 5-FU levels, may predict hematological toxicity and enable subsequent dose adjustments.