[Plasma concentrations of 5-fluorouracil and F-beta-alanine following oral administration of S-1, a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine, as compared with protracted venous infusion of 5-fluorouracil].
The pharmacokinetics and pharmacodynamics of oral S-1, a dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, were compared with those of protracted venous infusion (PVI) of 5-fluorouracil (5-FU). In all, 10 patients with gastric cancer received PVI of 5-FU at a dose of 250 mg/m2/day for 5 days. After a washout period of 9 days, the 10 patients received two divided doses daily for 28 days. S-1 was administered orally at about 9 a.m. and 7 p.m. Plasma concentrations of 5-FU and F-beta-alanine (FBAL) were measured for pharmacokinetic analysis, and the plasma uracil concentration was monitored as a surrogate marker of DPD inhibition in the same 10 patients on days 1-5 of PVI of 5-FU and on days 1-5 of oral S-1. The area under the curve (AUC0-10h) of 5-FU on day 5 was 728 +/- 113 ng x hr/ml for PVI of 5-FU and 1,364 +/- 374 ng x hr/ml for S-1. The median 5-FU PVI: S-1 ratio of the AUC0-10h of 5-FU was 1.9. The AUC0-10h of FBAL on day 5 of PVI of 5-FU was 9,465 +/- 3,225 ng x hr/ml, AUC0-10h, as compared with 1,725 +/- 605 ng x hr/ml on day 5 of S-1 treatment. The AUC0-10h of uracil on day 5 was 252 +/- 60 ng x hr/ml with PVI of 5-FU and 12,582 +/- 3,060 ng x hr/ml with S-1. The AUC0-10h of FBAL was markedly lower and plasma uracil concentrations were significantly higher for S-1 than for PVI of 5-FU, clearly demonstrating the effect of DPD inhibition.
Yamada
Yasuhide
Y
Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
D042943:Dihydrouracil Dehydrogenase (NADP) / Q000037:antagonists & inhibitors*; D004338:Drug Combinations; D005472:Fluorouracil / Q000008:administration & dosage / Q000097:blood*; D006801:Humans; D007262:Infusions, Intravenous; D007668:Kidney / Q000187:drug effects / Q000503:physiopathology; D010094:Oxonic Acid / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D013274:Stomach Neoplasms / Q000097:blood / Q000188:drug therapy*; D005641:Tegafur / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D014498:Uracil / Q000097:blood; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000097:blood
D004338:Drug Combinations; D015091:beta-Alanine; C079198:S 1 (combination); D005641:Tegafur; C032348:alpha-fluoro-beta-alanine; D014498:Uracil; D010094:Oxonic Acid; D042943:Dihydrouracil Dehydrogenase (NADP); D005472:Fluorouracil