AIMS To investigate the effect of ethanol intake on the whole enterohepatic circulation (EHC) of bile acids (BAs) and, more importantly, on pharmacokinetics of irinotecan. METHODS The present study utilized a mouse model administered by gavage with 0 (control), 240 mg/100 g (30%, v/v) and 390 mg/100 g (50%, v/v) ethanol for 6 weeks, followed by BA profiles in the whole EHC (including liver, gallbladder, intestine and plasma) and colon using ultra-high performance liquid chromatography with tandem mass spectrometry analysis. Pharmacokinetic parameters of irinotecan were measured after administration of irinotecan (i.v. 5 mg/kg) on alcohol-treated mice. RESULTS The results showed that compared with the control group, concentrations of most free-BAs, total amount of the three main forms of BAs (free-BA, taurine-BA and glycine-BA) and total BAs (TBAs) in 50% ethanol intake group were significantly increased, which are mostly attributed to the augmentation of free-BAs and taurine-BAs. Additionally, the TBAs in liver and gallbladder and the BA pool were markedly increased in the 30% ethanol intake group. Importantly, ethanol intake upregulated the expression of BA-related enzymes (Cyp7a1, Cyp27a1, Cyp8b1 and Baat) and transporters (Bsep, Mrp2, P-gp and Asbt) and downregulated the expression of transporter Ntcp and nuclear receptor Fxr in the liver and ileum, respectively. Additionally, 50% ethanol intake caused fairly distinct liver injury. Furthermore, the AUC0-24 h of irinotecan and SN38 were significantly reduced but their clearance was significantly increased in the disrupted EHC of BA by 50% ethanol intake. CONCLUSIONS The present study demonstrated that ethanol intake altered the expression of BA-related synthetases and transporters. The BA levels, especially the toxic BAs (chenodeoxycholic acid, deoxycholic acid and lithocholic acid), in the whole EHC were significantly increased by ethanol intake, which may provide a potential explanation to illuminate the pathogenesis of alcoholic liver injury. Most importantly, chronic ethanol consumption had a significant impact on the pharmacokinetics (AUC0-24 h and clearance) of irinotecan and SN38; hence colon cancer patients with chronic alcohol consumption treated with irinotecan deserve our close attention.

中文翻译：

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慢性酒精消耗增加了肠肝循环中的胆汁酸水平，降低了伊立替康的功效。

目的研究乙醇摄入对胆汁酸（BAs）整个肠肝循环（EHC）的影响，更重要的是对伊立替康的药代动力学的影响。方法本研究利用小鼠模型，分别灌胃0（对照组），240 mg / 100 g（30％，v / v）和390 mg / 100 g（50％，v / v）乙醇，持续6周。使用超高效液相色谱-串联质谱分析在整个EHC（包括肝脏，胆囊，肠和血浆）和结肠中的BA谱。在将伊立替康（iv 5 mg / kg）施用于酒精治疗的小鼠后，测量了伊立替康的药代动力学参数。结果结果表明，与对照组相比，大多数游离BAs的浓度，三种主要形式的BAs（游离BA，50％乙醇摄入组牛磺酸-BA和甘氨酸-BA）和总BAs（TBA）显着增加，这主要归因于游离BA和牛磺酸-BAs的增加。此外，在30％乙醇摄入组中，肝胆囊中的TBA和BA池显着增加。重要的是，乙醇摄入会上调肝和回肠中BA相关酶（Cyp7a1，Cyp27a1，Cyp8b1和Baat）和转运蛋白（Bsep，Mrp2，P-gp和Asbt）的表达，并下调转运蛋白Ntcp和核受体Fxr的表达。 ， 分别。此外，摄入50％的乙醇会引起明显的肝损伤。此外，伊立替康和SN38的AUC0-24 h显着减少，但在摄入50％乙醇的情况下，BA的EHC受到破坏，其清除率显着增加。结论本研究表明乙醇摄入改变了BA相关合成酶和转运蛋白的表达。通过摄入乙醇可以显着提高整个EHC中的BA水平，尤其是有毒的BAs（鹅去氧胆酸，脱氧胆酸和石胆酸），这可能为阐明酒精性肝损伤的发病机理提供了可能的解释。最重要的是，长期摄入乙醇对伊立替康和SN38的药代动力学（AUC0-24小时和清除率）有显着影响。因此，伊立替康治疗慢性饮酒的结肠癌患者值得我们密切关注。在整个EHC中，乙醇摄入显着增加了EHC，这可能为阐明酒精性肝损伤的发病机理提供了可能的解释。最重要的是，长期摄入乙醇对伊立替康和SN38的药代动力学（AUC0-24小时和清除率）有重大影响。因此，伊立替康治疗慢性饮酒的结肠癌患者值得我们密切关注。在整个EHC中，乙醇摄入显着增加了EHC，这可能为阐明酒精性肝损伤的发病机理提供了可能的解释。最重要的是，长期摄入乙醇对伊立替康和SN38的药代动力学（AUC0-24小时和清除率）有重大影响。因此，伊立替康治疗慢性饮酒的结肠癌患者值得我们密切关注。