Effect of dimethylnitrosamine-induced liver dysfunction on the pharmacokinetics of 5-fluorouracil after administration of S-1, an antitumour drug, to rats.
OBJECTIVE
The anti-tumour agent S-1 comprises tegafur (a prodrug of 5-fluorouracil; 5-FU), gimeracil (2-chloro-2,4-dihydroxypyridine (CDHP); a competitive inhibitor of 5-FU metabolism) and oteracil potassium. The effect of hepatic dysfunction induced by dimethylnitrosamine (DMN) on the pharmacokinetics of 5-FU after administration of S-1 to rats was investigated.


METHODS
S-1 (5 mg/kg) was administered intravenously and orally to rats with DMN-induced liver dysfunction. Plasma concentrations of S-1 components and 5-FU were measured by HPLC and LC/MS-MS. Blood tests and in-vitro enzymatic investigations were also conducted.


RESULTS
DMN treatment induced hepatic dysfunction and decreased the conversion of tegafur to 5-FU in the liver without altering renal function or dihydropyrimidine dehydrogenase activity. Following intravenous administration of S-1, the blood concentration-time profiles of CDHP were similar between control rats and rats with hepatic dysfunction, but the half-life of tegafur was significantly prolonged. The maximum plasma concentration (C(max)) of 5-FU was significantly reduced and the area under the blood concentration-time curve (AUC) was reduced by 22%. Following oral administration, the C(max) of tegafur, 5-FU and CDHP were significantly decreased and half-lives significantly increased. Hepatic dysfunction had a less pronounced effect on the AUC of 5-FU (13.6% reduction).


CONCLUSIONS
The pharmacokinetic profiles of tegafur, 5-FU and CDHP were altered by changes in the elimination rate of tegafur induced by a decrease in the conversion of tegafur to 5-FU. However, hepatic dysfunction had less of an effect on the AUC of 5-FU, which correlates with anti-tumour effect, after the oral administration of S-1.
Yoshisue
Kunihiro
K
Pharmacokinetics Research Laboratory, Tokushima Research Center, Taiho Pharmaceutical Co., Ltd, Tokushima, Japan. kuni-yoshisue@taiho.co.jp
Kanie
Shohei
S
Nishimura
Takako
T
Chikamoto
Junko
J
Nagayama
Sekio
S
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019540:Area Under Curve; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D042943:Dihydrouracil Dehydrogenase (NADP) / Q000378:metabolism; D004128:Dimethylnitrosamine; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008107:Liver Diseases / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D010094:Oxonic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics*
D000970:Antineoplastic Agents; D004338:Drug Combinations; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D004128:Dimethylnitrosamine; D005472:Fluorouracil