TY - JOUR T1 - Clinical pharmacology of combined oral uracil and ftorafur. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 936 LP - 940 VL - 20 IS - 6 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 Y1 - 1992/11/01 UR - http://dmd.aspetjournals.org/content/20/6/936.abstract N2 - 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. ER -