title: Effect of 5-fluorouracil treatment on SN-38 absorption from intestine in rats.
abstract: 5-Fluorouracil (5-FU)-based chemotherapies with irinotecan have been applied for the treatment of cancers, and a common dose-limiting toxicity is neutropenia and diarrhea. In this study, we investigated the effect of 5-FU treatment on expression levels of drug transporters for SN-38 transportation and SN-38 absorption from the intestine following 5-FU treatment. Expression levels of several drug transporters and nuclear receptors in rats after 5-FU treatment were evaluated. SN-38 absorption from the intestine was evaluated by SN-38 concentration levels in serum following SN-38 injection into the intestine of 5-FU treated rats. The levels of renal multidrug resistance protein 2 (Mrp2) on day 4 after treatment (400 mg/kg) showed significant upregulation, 359.2 ± 33.2% (mean ± S.E.) of control. Mrp2 levels in the intestine were downregulated to 26.2 ± 8.4% of control. 5-FU treatment (400 mg/kg) also significantly downregurated expression levels of P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) to 41.2 ± 14.7%, 15.7 ± 4.3% of control, respectively. To evaluate SN-38 absorption from the intestine, SN-38 was loaded in to the intestine on day 4 after 5-FU treatment. Pretreatment with 5-FU significantly increased SN-38 concentration in the blood 30, 60 and 90 min after SN-38 administration. The area under the curve for SN-38 in the 5-FU group was significantly higher than in vehicle groups. 5-FU treatment decreased expression levels of P-glycoprotein and Bcrp in intestine. The present study suggests that combination chemotherapy of 5-FU with irinotecan (CPT-11) may elevate SN-38 absorption from intestine.
authors: Education Research Center for Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Hokkaido University, Japan.
authors: Yoshihiko
authors: Y
authors: Shibayama
authors: Yoshitaka
authors: Y
authors: Iwashita
authors: Yoshimi
authors: Y
authors: Yoshikawa
authors: Tomoko
authors: T
authors: Kondo
authors: Ryuji
authors: R
authors: Ikeda
authors: Yasuo
authors: Y
authors: Takeda
authors: Takayuki
authors: T
authors: Osada
authors: Mitsuru
authors: M
authors: Sugawara
authors: Katsushi
authors: K
authors: Yamada
authors: Ken
authors: K
authors: Iseki
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D001835:Body Weight / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D002460:Cell Line; D017931:DNA Primers; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects*; D000077146:Irinotecan; D008297:Male; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D017931:DNA Primers; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000077146:Irinotecan; D005472:Fluorouracil; D002166:Camptothecin