Effect of cholecystectomy on bile acids as well as relevant enzymes and transporters in mice: Implication for pharmacokinetic changes of rifampicin

详细信息    查看全文

• 作者：Fan Zhang^a ; ^b ; Hongyan Qin^b ; Yanshu Zhao^a ; ^b ; Yuhui Wei^b ; Lili Xi^b ; Zhi Rao^b ; Jianping Zhang^b ; Yanrong Ma^b ; Yingting Duan^a ; ^b ; Xinan Wu^b ; ^{xinanwu6511@126.com}
• 关键词：Asbt ; apical sodium-dependent bile acids transporter ; BAs ; bile acids ; Bsep ; bile salt export pump ; β-MCA ; β-muricholic acid ; CA ; cholic acid ; CDCA ; chenodeoxycholic acid ; Cyp3a11 ; cytochrome P450 3a11 (human CYP3A4) ; Cyp7a1 ; cholesterol 7α-hydroxylase cytochrome P450 7a1 ; DCA ; deoxycholic acid ; Fxr ; farnesoid X receptor ; G- ; glycine conjugated bile acid ; HDCA ; hyodesoxycholic acid ; LCA ; lithocholic acid ; Mrp2 ; multidrug resistance-associated protein 2 ; NDCA ; demethylation deoxycholic acid ; NRs
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：141-153
• 全文大小：1996 K
• 卷排序：96

文摘

Long-term medical consequences of cholecystectomy are believed to be uncommon. It has been reported that bile acids (BAs) changed after cholecystectomy. As important signaling molecules, the alternations of BAs might favour the regulatory effect on enzymes and transporters involved in BAs physiological homeostasis at the transcriptional level, which could lead to pharmacokinetic changes of drugs. Here, we determined the effect of cholecystectomy on BAs, relevant enzymes and transporters and pharmacokinetic parameters of rifampicin, and explored the potential mechanisms at the transcriptional regulatory level via nuclear receptors.MethodsParameters of BAs in different specimens, mRNA and protein expression of enzymes, transporters and nuclear receptors that relate to BAs homeostasis in liver and ileum, and the pharmacokinetic character of rifampicin were measured in sham-operated and cholecystectomized mice.Key resultsCholecystectomy associated with considerable decreased BAs pool size that could attribute to increased fecal excretion. Most notably, as the Fxr and Pxr ligands, the alternations of hepatic and ileal individual BAs affected expression of enzymes Cyp3a11 and transporters Ntcp and Bsep in liver and Asbt in ileum significantly following cholecystectomy. Eventually, the rifampicin bioavailability was improved with depressed clearance in mice without gallbladders.ConclusionAs natural ligands for Fxr and Pxr, the alternations of individual BAs lead to the regulation of hepatic and ileal relevant enzymes and transporters after cholecystectomy. Especially, the down-regulation of hepatic Cyp3a11 suggests that undesirable pharmacokinetic alternations of drugs especially Cyp3a11 substrates like rifampicin might occur in phase with cholecystectomy.