Clinical pharmacology of combined oral uracil and ftorafur.
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.
Ho
D H
DH
Department of Medical Oncology, University of Texas M. D. Anderson Cancer Center, Houston 77030.
Covington
W P
WP
Pazdur
R
R
Brown
N S
NS
Kuritani
J
J
Newman
R A
RA
Raber
M N
MN
Krakoff
I H
IH
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics*; D005260:Female; D005472:Fluorouracil / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics*; D014498:Uracil / Q000008:administration & dosage / Q000493:pharmacokinetics*
D005641:Tegafur; D014498:Uracil; D005472:Fluorouracil