Comparison of 5-fluorouracil pharmacokinetics in patients receiving continuous 5-fluorouracil infusion and oral uracil plus N1-(2'-tetrahydrofuryl)-5-fluorouracil.
Plasma 5-fluorouracil (5-FU) levels were compared in the same patients after approximately equimolar doses (1.9 mmol/ m2/day) of 5-day continuous i.v. infusion of 5-FU (CIFU) and oral administration of a formulation of two combined pharmacological agents, uracil (U) plus N1-(2'-tetrahydrofuryl)-5-fluorouracil (ftorafur or FT), a prodrug of 5-FU. Ten patients received CIFU for 5 days, then, after a week wash-out period, began the 28-day oral UFT regimen, which was given in three daily divided doses. Following 1 h of CIFU, the plasma 5-FU levels reached a steady state of 0.6+/-0.2 microM (mean+/-SD; day 1), which was maintained for the entire 5-day infusion period (0.6+/-0.1 microM). In contrast, the maximum 5-FU concentrations (Cpmax) generated from oral UFT at 1 h after dose administration on days 1 and 5 were 2.1+/-1.5 microM and 2.3+/-1.9 microM, respectively, which were higher than the steady-state levels during CIFU. These high 5-FU levels disappeared with an apparent elimination half-life (tl/2,beta) of 5.2+/-2.4 h (day 1) and 7.2+/-3.9 h (day 5). On day 1 of both regimens, CIFU patients had significantly larger 5-FU area under the concentration versus time curve (AUC0-8h) values (4.4+/-1.3 microM.h) than the AUC value when they received the UFT regimen (2.6+/-1.7 microM.h; P = 0.02). However, by day 5, there were no significant differences between AUC0-8 h values in patients receiving CIFU and UFT, respectively (4.8+/-1.5 microM.h versus 3.8+/-2.2 microM.h; P = 0.30)]. On day 5, the average concentration of the metabolite 5-FU at steady-state (Css,aver) within dose interval of 8 h (0.48+/-0.28 microM) for the oral UFT treatment is comparable with the Cpss values of 5-FU from CIFU-treated patients. The post-UFT generated 5-FU pharmacokinetic parameters (higher Cp(mx, comparable Css,aver, equal AUC values, and longer apparent t1/2,beta of 5-FU) may make oral UFT a preferred method of delivering this fluoropyrimidine over CIFU. In addition, oral UFT would eliminate the incidence of venous thrombosis and catheter-related infections sometimes seen in patients treated with CIFU. Furthermore, the convenience and decreased cost of oral administration may be preferable for many patients, particularly those receiving 5-FU for palliation.
Ho
D H
DH
Department of Clinical Investigation, The University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
Pazdur
R
R
Covington
W
W
Brown
N
N
Huo
Y Y
YY
Lassere
Y
Y
Kuritani
J
J
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D000284:Administration, Oral; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D014498:Uracil / Q000008:administration & dosage / Q000494:pharmacology*
D000964:Antimetabolites, Antineoplastic; D011355:Prodrugs; D005641:Tegafur; D014498:Uracil; D005472:Fluorouracil