The effect of food on the pharmacokinetics of S-1 after single oral administration to patients with solid tumors.
OBJECTIVE
The purpose is to determine the effect of food on the bioavailability of S-1, an oral formulation of the 5-fluorouracil (5FU) prodrug Ftorafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), a dihydropyrimidine dehydrogenase inhibitor, and oxonic acid (an inhibitor of 5FU phosphoribosylation in normal gut mucosa) in a molar ratio of 1:0.4:1.


METHODS
Eighteen patients received a single dose of S-1 of 35 mg/m(2) with (535-885 kcal) or without food in a crossover study design: in arm A without breakfast on day -7 and with breakfast on day 0 and in arm B the reversed sequence. Blood samples were taken before and after S-1 administration. This food effect was evaluated according to the Food and Drug Administration guidelines using log-transformed data.


RESULTS
Pharmacokinetic parameters for 5FU without breakfast were as follows: Tmax, 107 min; Cmax, 1.60 microm; area under the plasma concentration-time curve (AUC) 441 microm x min; and T(1/2), 104 min. Fasting decreased Tmax of FT, 5FU, CDHP, and oxonic acid significantly (P < 0.006) and increased the Cmax (P < 0.013). The food/fast ratio for the AUC of FT was not different, which for 5FU was 0.84 (P = 0.041), for CDHP was 0.89 (P = 0.191), for oxonic acid was 0.48 (P < 0.0005), and for cyanuric acid, the breakdown product of oxonic acid, was 5.1 (P = 0.019). Accumulation of uracil, indicative for dihydropyrimidine dehydrogenase inhibition, was not affected, as well as the T(1/2) of FT, 5FU, CDHP, and oxonic acid. Evaluation of the log-transformed data demonstrated that the 90% confidence interval for the food/fast ratio for the Cmax and AUC of FT, 5FU, CDHP, and uracil were within 70-143% and 80-125%, respectively, indicating no food effect. Only for oxonic acid and cyanuric acid were these values outside this interval.


CONCLUSIONS
Food intake affected only the pharmacokinetics of the S-1 constituent oxonic acid but not of FT, CDHP, and 5FU. Because oxonic acid is included to protect against gastrointestinal toxicity, this observation might affect the gastrointestinal toxicity and thus the efficacy of S-1.
Peters
Godefridus J
GJ
Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands. gjpeters@vumc.nl
Noordhuis
Paul
P
Van Groeningen
Cornelis J
CJ
Giaccone
Giuseppe
G
Holwerda
Ulbe
U
Voorn
Daphne
D
Schrijvers
Ad
A
Schornagel
Jan H
JH
Beijnen
Jos H
JH
Fumoleau
Pierre
P
Schellens
Jan H M
JH
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D018592:Cross-Over Studies; D004435:Eating; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D005502:Food; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010094:Oxonic Acid / Q000008:administration & dosage*; D010766:Phosphorylation; D011725:Pyridines / Q000008:administration & dosage*; D005641:Tegafur / Q000008:administration & dosage*; D013997:Time Factors
C417063:5-chlorodihydroxypyridine; D000964:Antimetabolites, Antineoplastic; D011725:Pyridines; D005641:Tegafur; D010094:Oxonic Acid; D005472:Fluorouracil