Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor agent in animal model and in patients with impaired renal function.
OBJECTIVE
S-1 is a novel oral fluorouracil antitumor drug that combines tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD), and potassium oxonate (Oxo). As 50% of CDHP is excreted in the urine, renal dysfunction may directly affect the DPD inhibitory effect and lead to increased 5-fluorouracil (5-FU) concentrations. We sought to determine the influence of impaired renal function on the pharmacokinetics of S-1 in an animal model and in patients with gastric cancer.


METHODS
An experimental renal failure model induced by cisplatin was developed in rabbits, and plasma concentrations of FT, 5-FU, CDHP and Oxo were determined after S-1 injection. Four patients with various degrees of renal impairment with unresectable gastric cancer were recruited to the study, and the pharmacokinetics in these four patients were analyzed following single and consecutive S-1 administrations.


RESULTS
In experimental renal failure, plasma clearance of CDHP and 5-FU was retarded corresponding to the degree of renal impairment and there was a close correlation between creatinine clearance (CLcr) and plasma CDHP and 5-FU clearance. In the single administration study, half standard dose was used in three patients (CLcr > or = 50 ml/min) and one-third in the other (CLcr <50 ml/min). In patients with CLcr more than 75 ml/min, C(max), T(max), AUC((0-infinity)), and T(1/2) of 5-FU and CDHP were not different between single and consecutive administrations. In contrast, in patients with mild and moderate renal dysfunction (CLcr 55 and 36 ml/min, respectively), the T(1/2) values of CDHP with consecutive administrations (7.6 and 15.3 h, respectively) were longer than the values with single administration (4.6 and 8.2 h, respectively). The T(1/2) of 5-FU was 5.7 h with single administration and 8.5 h with consecutive administration in patients with moderate renal impairment. The AUC((0-infinity)) of 5-FU with consecutive administrations (3089.7 ng.h/ml) was far greater than with single administration (430.4 ng.h/ml). There was also a strong correlation between CLcr and plasma CDHP clearance. Based on the pharmacokinetics following multiple consecutive administrations, S-1 administration resulted in no severe adverse reactions in any of the four patients.


CONCLUSIONS
CDHP clearance was prolonged in the presence of renal impairment, leading to a delayed T(1/2), and high AUC of 5-FU. These findings demonstrate that administration of S-1 to patients with impaired renal function may need individualized dosing and pharmacokinetic monitoring.
Department of Surgery and Clinical Oncology (E2), Graduate School of Medicine, Osaka University, Suita, Japan. mikeda@surg2.med.osaka-u.ac.jp
Masataka
M
Ikeda
Hiroshi
H
Furukawa
Hiroshi
H
Imamura
Jyunzo
J
Shimizu
Hideyuki
H
Ishida
Seizo
S
Masutani
Masayuki
M
Tatsuta
Takatoshi
T
Kawasaki
Takashi
T
Satomi
D000368:Aged; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics*; D002945:Cisplatin / Q000633:toxicity; D004195:Disease Models, Animal; D004338:Drug Combinations; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008875:Middle Aged; D010094:Oxonic Acid / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics*; D011817:Rabbits; D051437:Renal Insufficiency / Q000139:chemically induced / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism; D005641:Tegafur / Q000493:pharmacokinetics*
D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D002945:Cisplatin