Effect of 5-Fluorouracil Treatment on SN-38 Absorption from Intestine in Rats
Effect of 5-Fluorouracil Treatment on SN-38 Absorption from Intestine in Rats
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DOI：
10.1248/bpb.34.1418
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发表时间：
2011-09-01
影响因子：
2
通讯作者：
Iseki, Ken
中科院分区：
文献类型：
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作者：
Shibayam, Yoshihiko;Iwashita, Yoshitaka;Iseki, Ken
基于 5-氟尿嘧啶 (5-FU) 的伊立替康化疗已用于治疗癌症，常见的剂量限制性毒性是中性粒细胞减少和腹泻。在这项研究中，我们研究了 5-FU 治疗对 5-FU 治疗后 SN-38 转运和 SN-38 从肠道吸收的药物转运蛋白表达水平的影响。评估了 5-FU 治疗后大鼠体内几种药物转运蛋白和核受体的表达水平。 SN-38从肠道的吸收通过将SN-38注射到5-FU处理的大鼠的肠道后血清中的SN-38浓度水平来评估。治疗（400 mg/kg）后第 4 天，肾多药耐药蛋白 2 (Mrp2) 水平显着上调，为对照的 359.2 +/- 33.2%（平均值 +/- S.E.）。肠道中的 Mrp2 水平下调至对照的 26.2 +/- 8.4%。 5-FU治疗(400 mg/kg)还显着下调P-糖蛋白(P-gp)和乳腺癌抗性蛋白(Bcrp)的表达水平，分别至对照的41.2 +/- 14.7%、15.7 +/- 4.3%。为了评估 SN-38 从肠道的吸收，在 5-FU 治疗后第 4 天将 SN-38 加载到肠道中。 SN-38给药后30、60和90分钟，用5-FU预处理显着增加了血液中SN-38的浓度。 5-FU 组中 SN-38 的曲线下面积显着高于赋形剂组。 5-FU治疗降低了肠道中P-糖蛋白和Bcrp的表达水平。目前的研究表明，5-FU 与伊立替康 (CPT-11) 的联合化疗可能会增加肠道对 SN-38 的吸收。
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.