Rifaximin is a gut-specific human pregnane X receptor activator

被引:113
作者
Ma, Xiaochao
Shah, Yatrik M.
Guo, Grace L.
Wang, Ting
Krausz, Kristopher W.
Idle, Jeffrey R.
Gonzalez, Frank J.
机构
[1] NCI, Met Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA
[2] Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA
[3] Charles Univ Prague, Fac Med 1, Inst Pharmacol, Prague, Czech Republic
关键词
D O I
10.1124/jpet.107.121913
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Rifaximin, a rifamycin analog approved for the treatment of travelers' diarrhea, is also beneficial in the treatment of multiple chronic gastrointestinal disorders. However, the mechanisms contributing to the effects of rifaximin on chronic gastrointestinal disorders are not fully understood. In the current study, rifaximin was investigated for its role in activation of the pregnane X receptor ( PXR), a nuclear receptor that regulates genes involved in xenobiotic and limited endobiotic deposition and detoxication. PXR- humanized ( hPXR), Pxr- null, and wild- type mice were treated orally with rifaximin, and rifampicin, a well characterized human PXR ligand. Rifaximin was highly concentrated in the intestinal tract compared with rifampicin. Rifaximin treatment resulted in significant induction of PXR target genes in the intestine of hPXR mice, but not in wild- type and Pxr- null mice. However, rifaximin treatment demonstrated no significant effect on hepatic PXR target genes in wild- type, Pxr- null, and hPXR mice. Consistent with the in vivo data, cell- based reporter gene assay revealed rifaximin- mediated activation of human PXR, but not the other xenobiotic nuclear receptors constitutive androstane receptor, peroxisome proliferator- activated receptor ( PPAR)alpha, PPAR gamma, and farnesoid X receptor. Pretreatment with rifaximin did not affect the pharmacokinetics of the CYP3A substrate midazolam, but it increased the C max and decreased T-max of 1'- hydroxymidazolam. Collectively, the current study identified rifaximin as a gut- specific human PXR ligand, and it provided further evidence for the utility of hPXR mice as a critical tool for the study of human PXR activators. Further human studies are suggested to assess the potential role of rifaximin- mediated gut PXR activation in therapeutics of chronic gastrointestinal disorders.
引用
收藏
页码:391 / 398
页数:8
相关论文
共 40 条
[21]   2004 Drug Approval Highlights FDA Update [J].
Laustsen, Gary ;
Wimmett, Lynn .
NURSE PRACTITIONER, 2005, 30 (02) :14-16
[22]  
Loguercio C, 2003, Minerva Gastroenterol Dietol, V49, P53
[23]   The pregnane X receptor gene-humanized mouse:: A model for investigating drug-drug interactions mediated by cytochromes P450 3A [J].
Ma, Xiaochao ;
Shah, Yatrik ;
Cheung, Connie ;
Guo, Grace L. ;
Feigenbaum, Lionel ;
Krausz, Kristopher W. ;
Idle, Jeffrey R. ;
Gonzalez, Frank J. .
DRUG METABOLISM AND DISPOSITION, 2007, 35 (02) :194-200
[24]   Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver [J].
Maher, JM ;
Cheng, XG ;
Slitt, AL ;
Dieter, MZ ;
Klaassen, CD .
DRUG METABOLISM AND DISPOSITION, 2005, 33 (07) :956-962
[25]   Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy:: results of a randomized, double-blind, doubledummy, controlled clinical trial [J].
Mas, A ;
Rodés, J ;
Sunyer, L ;
Rodrigo, L ;
Planas, R ;
Vargas, V ;
Castells, L ;
Rodríguez-Martínez, D ;
Fernández-Rodríguez, C ;
Coll, I ;
Pardo, A .
JOURNAL OF HEPATOLOGY, 2003, 38 (01) :51-58
[26]   Steroid and xenobiotic receptor (SXR), cytochrome P450 3A4 and multidrug resistance gene 1 in human adult and fetal tissues [J].
Miki, Y ;
Suzuki, T ;
Tazawa, C ;
Blumberg, B ;
Sasano, H .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2005, 231 (1-2) :75-85
[27]   Management of diverticular disease: Is there room for rifaximin? [J].
Papi, C ;
Koch, M ;
Capurso, L .
CHEMOTHERAPY, 2005, 51 :110-114
[28]  
Pistoia M A, 2004, Eur Rev Med Pharmacol Sci, V8, P283
[29]   Genetic profiling defines the xenobiotic gene network controlled by the nuclear receptor pregnane X receptor [J].
Rosenfeld, JM ;
Vargas, R ;
Xie, W ;
Evans, RM .
MOLECULAR ENDOCRINOLOGY, 2003, 17 (07) :1268-1282
[30]   Dual role of orphan nuclear receptor pregnane X receptor in bilirubin detoxification in mice [J].
Saini, SPS ;
Mu, Y ;
Gong, HB ;
Toma, D ;
Uppal, H ;
Ren, SR ;
Li, S ;
Poloyac, SM ;
Xie, W .
HEPATOLOGY, 2005, 41 (03) :497-505