title: Postgastrectomy pharmacokinetic changes of S-1 in patients with localized advanced gastric cancer.
abstract: S-1 is an oral 5-fluorouracil agent containing tegafur, 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate. This study explored the pharmacokinetics of S-1 and pharmacokinetic changes after gastric surgery in patients with resectable gastric cancer who received pre- and postoperative S-1 plus docetaxel. Serial blood was drawn before and after gastrectomy from 37 patients for pharmacokinetic analysis. The pharmacokinetics of tegafur, 5-fluorouracil, and CDHP were analyzed by noncompartmental analysis (NCA) methods and by modeling. In modeling analysis, CHDP concentrations were incorporated in the model as a time-varying covariate that inhibits the clearance of 5-fluorouracil following an inhibitory Emax model. In NCA, the pharmacokinetics of tegafur and 5-FU before and after gastric surgery were similar, although average maximum concentrations of 5-FU were decreased with statistical significance after gastrectomy. Median Tmax of tegafur was shorter after surgery without statistical significance. In modeling analysis, tegafur was best fitted by mixed zero and first-order absorption. The only difference in the final pharmacokinetic model around gastrectomy was the presence of an absorption lag of 0.23 hours before surgery. Incorporation of CDHP concentrations significantly improved the model. Although some pharmacokinetic results showed statistically significant changes after gastrectomy, these differences seem to be too small to have any clinical implication.
authors: Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
authors: Hyeong-Seok
authors: HS
authors: Lim
authors: Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
authors: Keun Won
authors: KW
authors: Ryu
authors: Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
authors: Jun Ho
authors: JH
authors: Lee
authors: Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
authors: Young-Woo
authors: YW
authors: Kim
authors: Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
authors: Il
authors: I
authors: Ju Choi
authors: Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
authors: Mi-Jung
authors: MJ
authors: Kim
authors: Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.
authors: Young-Iee
authors: YI
authors: Park
authors: Department of Clinical Pharmacology and Therapeutics, Ulsan University College of Medicine, Asan Medical Center, Seoul, Republic of Korea.
authors: Aekyung
authors: A
authors: Hwang
authors: Center for Gastric Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Republic of Korea.|Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
authors: Sook Ryun
authors: SR
authors: Park
mesh_terms: D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000097:blood / Q000493:pharmacokinetics*; D004338:Drug Combinations; D005260:Female; D005743:Gastrectomy; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010094:Oxonic Acid / Q000097:blood / Q000493:pharmacokinetics*; D011725:Pyridines / Q000097:blood; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000601:surgery; D005641:Tegafur / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D004338:Drug Combinations; D011725:Pyridines; C079198:S 1 (combination); D005641:Tegafur; D010094:Oxonic Acid; C104201:gimeracil
keywords: NONMEM; S-1; gastrectomy; modeling; pharmacokinetics