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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (X.M., Y.M.S., T.W., K.W.K., F.J.G.); Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas (G.L.G.); and Institute of Pharmacology, First Faculty of Medicine, Charles University, Prague, Czech Republic (J.R.I.)
Received February 24, 2007; accepted April 17, 2007.
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Abstract |
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, PPAR
, and farnesoid X receptor. Pretreatment with rifaximin did not affect the pharmacokinetics of the CYP3A substrate midazolam, but it increased the Cmax and decreased Tmax 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.
). RIFax was shown to be a general antibiotic that acts to inhibit bacterial RNA synthesis. Interestingly, accumulated data revealed the potential value of RIFax in the treatment of chronic gastrointestinal disorders. RIFax was effective in both acute and chronic hepatic encephalopathy (Loguercio et al., 2003; Mas et al., 2003). Several recent clinical trails have recommended the use of RIFax for prevention of the main complications in patients with diverticular disease (Latella et al., 2003; Pistoia et al., 2004; Papi et al., 2005). In patients with gas-related symptoms, the colonic production of H2 is increased, and RIFax significantly reduces this production and the excessive number of flatus episodes (Di Stefano et al., 2000). A combination of RIFax and ciprofloxacin was effective in patients with active chronic, treatment-resistant pouchitis (Gionchetti et al., 1999; Abdelrazeq et al., 2005). In addition, RIFax was beneficial in ulcerative colitis and Crohn's disease (CD), two chronic inflammatory diseases generally referred to as inflammatory bowel diseases (IBDs). Despite the differences in dose and duration, RIFax was beneficial in active ulcerative colitis, mild-to-moderate CD as well as prevention of postoperative recurrence of CD (Shafran and Johnson, 2005; Gionchetti et al., 2006; Guslandi et al., 2006). The mechanism contributing to the beneficial effects of RIFax in chronic gastrointestinal disorders are not fully understood. Recently, it was revealed that the susceptibility to IBD was strongly associated with genetic variation in the pregnane X receptor gene (PXR; NR1I2), a member of the nuclear receptor family (Langmann et al., 2004; Dring et al., 2006). In a dextran sulfate sodium (DSS)-induced IBD mouse model, pregnenolone 16-carbonitrile (PCN), a rodent-specific PXR ligand, demonstrated a protective role in DSS-induced colitis (Shah et al., 2007).
In the current study, RIFax was investigated for its role in activation of the PXR. PXR is an integral component of the body's defense mechanism involved in endogenous and xenobiotic detoxication (Kliewer et al., 2002). PXR is activated by a broad spectrum of xenobiotics, including prescription drugs, herbal supplements, pesticides, endocrine disrupters, and other environmental contaminants (Carnahan and Redinbo, 2005). PXR activation regulates a number of genes involved in the metabolism and excretion of xenobiotics, including toxic chemicals (Kliewer, 2003; Rosenfeld et al., 2003; Sonoda et al., 2005). Several independent observations have led to the hypothesis of RIFax as a potential human gut PXR ligand: 1) the high degree of structural similarity between RIFax and rifampicin (RIF) (Fig. 1, A and B), a well known human PXR ligand (Bertilsson et al., 1998); 2) the high expression of PXR in human gut (Miki et al., 2005) and the high RIFax concentration in gut following oral treatment (Jiang et al., 2000); and 3) the induction CYP3A4, a bona fide PXR target gene, following RIFax incubation in a human hepatocyte model (http://wwwsalix.com/). To test this hypothesis, a novel animal model was used, PXR-humanized (hPXR) mice, in which the entire human PXR gene was reintroduced into the Pxr-null background (Ma et al., 2007). The present study identified RIFax as a human PXR ligand, and it provides further evidence for the utility of hPXR mice as a critical tool for human PXR study.
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Animals and Treatments. hPXR, Pxr-null, and wild-type (WT) mice were maintained under a standard 12-h light/12-h dark cycle with water and chow provided ad libitum. Pxr-null and hPXR mice were described previously (Staudinger et al., 2001; Ma et al., 2007). To investigate the potential role of RIFax in PXR activation, 2- to 4-month-old male hPXR, Pxr-null, and WT mice were treated orally with 25 mg/kg/day RIFax for 3 days. RIF, a specific human PXR ligand, was used as positive control at 25 mg/kg/day (p.o.) for 3 days. Corn oil was used as vehicle for both RIF and RIFax treatment. All mice were killed by CO2 asphyxiation 24 h after the last dose. Liver and small intestine were collected and frozen at -80°C for further analysis. Handling was in accordance with animal study protocols approved by the National Cancer Institute Animal Care and Use Committee.
RIFax Pharmacokinetics and Its Distribution in Intestinal Tract. For pharmacokinetic analysis, WT, Pxr-null, and hPXR mice were treated with 10 mg/kg RIF or RIFax by oral gavage. Corn oil was used as vehicle for both RIF and RIFax treatment. Blood samples were collected from suborbital veins using heparinized tubes at predose and 0.25, 0.5, 1.5, 3, 6, 9, 12, 24, and 48 h after the administration. To compare the metabolic profiles of RIFax and RIF, 10 mg/kg RIFax and RIF were administered by i.v. and i.p. For i.p. injections, corn oil was used as vehicle for both RIF and RIFax, and blood samples were collected from suborbital veins at predose and 0.25, 0.5, 1, 2, 4, 8, 24, and 48 h after the administration. For i.v. injections, 30% polyethylene glycol (wt 400) was used as vehicle for both RIF and RIFax, and blood samples were collected from suborbital veins at predose and 0.0833, 0.25, 0.5, 1, 2, 4, 8, 24, and 48 h after the administration. Serum was separated by centrifugation at 8000g for 10 min. Fifty microliters of serum was mixed with 150 µl of methanol, vortexed twice for 20 s, and centrifuged at 14,000 rpm for 10 min at 4°C. The upper organic layer was then transferred to an autosampler vial for RIF or RIFax detection by LC-MS/MS using an API2000 SCIEX triple-quadrupole tandem mass spectrometer (Applied Biosystems/MDS Sciex, Foster City, CA). Pharmacokinetic parameters of RIF and RIFax were estimated from the serum concentration-time data by a noncompartmental approach using WinNonlin (Pharsight, Mountain View, CA). The maximum concentration in serum (Cmax) was obtained from the original data. The area under the serum concentration-time curve (AUC)0–48 h was calculated by the trapezoidal rule. To detect the distribution in intestinal tract, mice were treated with 10 mg/kg RIFax or RIF (p.o.). At 1.5, 3, 6, 9, 12, 24, and 48 h after administration, the mice were killed, and the contents in different segments of the intestinal tract were collected. Intestinal contents were weighted and homogenized in 100 mg/ml methanol. The homogenate was centrifuged at 14,000 rpm for 10 min at 4°C. The upper organic layer was then transferred to an autosampler vial for RIF or RIFax detection by LC-MS/MS.
Analysis of RIFax and RIF by LC-MS/MS. RIFax and RIF were determined by LC-MS/MS, carried out using a high-performance liquid chromatography system consisting of a PerkinElmer Series 200 quaternary pump, vacuum degasser, and autosampler with a 100-µl loop interfaced to LC-MS/MS as noted above. RIFax and RIF were separated on a Luna C18 (50 x 4.6 mm i.d.) column (Phenomenex, Torrance, CA). The flow rate through the column at ambient temperature was 0.25 ml/min with 85% methanol and 15% H2O containing 0.1% formic acid. The mass spectrometer was operated in the turbo ion spray mode with positive ion detection. The turbo ion spray temperature was maintained at 300°C, and a voltage of 4.8 kV was applied to the sprayer needle. N2 was used as the turbo ion spray and nebulizing gas. Detection and quantification were performed using the multiple reactions monitoring mode, with m/z 786.3/754.5 for RIFax and m/z 823.5/791.5 for RIF.
Pharmacokinetic Analysis of MDZ in hPXR Mice Pretreated with RIFax. hPXR mice were pretreated with or without 10 mg/kg RIFax once daily for 3 days. Corn oil was used as the vehicle for RIFax treatment. Twenty-four hours after the last dose of RIFax, mice were administered 2.5 mg/kg MDZ by oral gavage. Blood samples were collected from suborbital veins using heparinized tubes at predose and 5, 10, 20, 30, 60, and 90 min after administration of MDZ. Serum was separated by centrifugation at 8000g for 10 min. For MDZ and 1'-OH-MDZ extraction, 50 µl of serum was mixed with 150 µl of phosphate-buffered saline, 200 µl of ethyl acetate, and 200 µl of methyl t-butyl ether. The mixture was centrifuged at 3000 rpm for 5 min at 4°C. The organic layer was then transferred to a new tube, dried with N2, and reconstituted in 100 µl of 70% aqueous methanol and 30% H2O containing 0.1% formic acid. MDZ and 1'-OH-MDZ were detected by LC-MS/MS, as described previously (Ma et al., 2007). Pharmacokinetic parameters for MDZ and 1'-OH-MDZ were estimated from the plasma concentration-time data by a noncompartmental approach using WinNonlin (Pharsight). The AUC0–90 min was calculated by the trapezoidal rule. The Cmax and its corresponding time (Tmax) were obtained from the original data.
Quantitative Real-Time Polymerase Chain Reaction Analysis of PXR Target Genes. The following PXR target genes were analyzed by quantitative real-time polymerase chain reaction (qPCR): cytochrome P450 3A11 (CYP3A11), glutathione S-transferase (GSTA)1, multidrug resistance protein (MRP)2, and organic anion transporting polypeptide (OATP)2 (Guo et al., 2002; Kast et al., 2002; Rosenfeld et al., 2003). RNA was extracted from different tissues using TRIzol reagent (Invitrogen, Carlsbad, CA). qPCR was performed using cDNA generated from 1 µg of total RNA with SuperScript II Reverse Transcriptase kit (Invitrogen). Primers were designed for qPCR using the Primer Express software (Applied Biosystems, Foster City, CA); primer sequences are listed in Table 1. Polymerase chain reaction reactions were carried out using SYBR Green PCR master mix (SuperArray) in an ABI Prism 7900HT Sequence Detection System (Applied Biosystems). Values were quantified using the comparative cycle threshold (CT) method, and samples were normalized to 
-actin.
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Cell-Based Reporter Assay. A hepG2 cell line (DPX2) with stable expression of recombinant human PXR and a PXR-response element cloned in a luciferase vector was obtained from Puracyp Inc. (Carlsbad, CA). The construction and validation of the cell lines were reported previously (Yueh et al., 2005). The cells were seeded according to the distributor's instructions. RIFax (1, 10, and 100 µM) was added to the culturing medium, and 10 µM RIF was used as positive control. The activation of PXR was determined by measuring the firefly luciferase activity 24 h later, followed by normalization of luciferase activity by protein concentrations. For cell-based reporter assay of nuclear receptors CAR, PPAR, PPAR, and FXR, HCT116 cells were plated on 24-well plates (5 x 104 cells/well, cultured in Dulbecco's modified Eagle's medium containing 10% fetal bovine serum), and transfected with the various expression vectors using FuGENE transfection reagent (Roche Diagnostics, Indianapolis, IN). The mouse PPAR and CAR vectors were described in previous reports (Kliewer et al., 1992; Swales et al., 2005). The mouse FXR vector was provided by Dr. Christopher J. Sinal (Dalhousie University, Halifax, NS, Canada). After 24 h post-transfection, the cells were incubated with vehicle (DMSO) and 10 µM RIFax for 24 h. We used 250 nM 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, 10 µM Wy-14,643, 10 µM rosiglitazone, and 25 µM GW4064 as positive controls for mouse CAR, PPAR, PPAR, and FXR, respectively. A standard dual luciferase assay was used and normalized to a cotransfected control reporter (Promega, Madison, WI). Each in vitro assay was repeated at least three times.
Statistical Analysis. All values are expressed as the mean ± S.D., and data were analyzed by two-tailed Student's t test. p < 0.05 was regarded as significantly different between groups.
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70-fold lower than that of 2.75 µM RIF. The AUC0–48 h of serum RIFax was 300-fold lower than that of RIF (Fig. 2A). However, for intestinal tract distribution, the RIFax concentration was significantly higher than that of RIF. In the small intestine, The RIF concentration was below 20 µg/g at all time points measured (Fig. 2B). For RIFax, the concentration was 160 µg/g, and it lasted up to 9 h after administration. The RIFax intestinal tract distribution in the cecum (Fig. 2C) and colon (Fig. 2D) was similar to that of the small intestine. No significant difference in RIFax metabolism was found among WT, Pxr-null, and hPXR mice after oral treatment. The Cmax values of RIFax (p.o. treatment) in WT, Pxr-null, and hPXR mice are shown in Fig. 2E. RIFax is well known as nonabsorbable rifamycin by oral treatment. By i.p. injection, RIFax was not well absorbed, and the bioavailability was significant lower than that of RIF (Fig. 2, F and G). Differences in metabolic profiles between RIFax and RIF were observed after i.v. treatment as ultrashort t1/2 and low AUC for RIFax compared with RIF (Fig. 2H).
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). Due to the high distribution of RIFax in the intestinal tract and expression of PXR in the gut, the effect of RIFax on gut PXR target genes was investigated by qPCR. In the small intestine of hPXR mice treated with RIFax, CYP3A11, GSTA1, MRP2, and OATP2 were all up-regulated (Fig. 3A). Intestinal CYP3A11 was increased 4-fold compared with vehicle-treated hPXR mice, whereas expression was inhibited in WT mice, and no significant change was observed in Pxr-null mice (Fig. 3, B and C). Intestinal GSTA1 mRNA was up-regulated in all three mouse strains after RIFax treatment, with 87, 74, and 172% increases noted in WT, Pxr-null, and hPXR mice, suggesting that the Gsta1 gene may not be a direct PXR target but that it may be elevated by an indirect mechanism. One possible explanation for the effect of RIFax on GSTA1 is the antibiotic activity of RIFax. In the current study, RIFax was administered orally at 25 mg/kg for 3 days, which may change the gut bacterial composition and indirectly effect GSTA1 expression. A slight but significant up-regulation of intestinal MRP2 mRNA was noted in hPXR mice after RIFax treatment, whereas its expression was significantly suppressed in WT mice, with no change observed in Pxr-null mice (Fig. 3, B and C). MRP2, which was reported to be activated by RIF and PCN in human and rat hepatocytes, respectively (Kast et al., 2002), was not markedly induced by RIF in liver and only modestly induced by RIF or RIFax in the gut in the current study. Indeed, others found that MRP2 is not significantly induced by mouse PXR ligands such as PCN (Maher et al., 2005). The finding that MRP2 is not induced by RIF in the hPXR mice suggests a possible species difference in the cis-elements controlling the Mrp2 gene between humans and mice. Intestinal OATP2 mRNA was increased 3.4-fold in hPXR mice after RIFax treatment, but no significant induction of this mRNA was noted in both WT and Pxr-null mice (Fig. 3, B and C). As expected, RIF also induced the four mRNAs in intestine but the extent of induction was less than that observed with RIFax (Fig. 3D). In contrast, RIF produced a significant induction of CYP3A11, GSTA1, and OATP2 in liver, whereas only GSTA1 mRNA was increased in the liver of RIFax-treated hPXR mice (Fig. 3, E and F). These data indicate that RIFax is a gut-specific human PXR ligand.
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Human PXR Activation by RIFax in a Cell-Based Reporter Assay. A dose-dependent increase in luciferase activity was observed in a cell-based reporter assay for hPXR activation by RIFax. Incubation with 1, 10, and 100 µM RIFax in the hPXR reporter system produced a 2.1-, 6.7-, and 25.2-fold increase, respectively, versus DMSO control (Fig. 4A). RIFax at 100 nM had no significant effect on hPXR, whereas 10 µM RIFax produced no significant change in luciferase activity in the presence of PPAR, PPAR, CAR, and FXR (Fig. 4B).
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200 µM) intestinal content. In humans, after 3 days of RIFax treatment (800 mg daily p.o.), the RIFax concentration was approximately 8 mg/g (10,000 µM) stool (Jiang et al., 2000), which indicated an extremely high concentration of RIFax exposure in the intestine. The effect of RIFax on gut PXR, but not the liver receptor, was probably related to its poor absorption. The metabolic profiles of RIFax in this study are consistent with previous studies, as high concentrations of RIFax in intestinal tract with only minor distribution in the blood (Venturini, 1983; Cellai et al., 1984); this was independent of PXR expression in the gut, indicating that lack of absorption is not due to PXR-induced metabolism. In humans, RIFax absorption is also negligible after oral administration. After a single oral dose of 400 mg of RIFax, the plasma RIFax concentration was below the detection limit of 2 ng/ml. In urine, very small amounts of the unchanged molecule were detected that were <0.01% of the administered dose (Descombe et al., 1994). Thus, the current study indicates that during clinical use, RIFax functions as an antibiotic and also as a PXR activator in the gut.
The identification of RIFax as human PXR ligand provides new insight into the role of RIFax in pharmacology and therapeutics. PXR, a member of the nuclear receptor family of ligand-activated transcription factors, is an integral component of the body's defense mechanism involved in the detoxication of xenobiotics (Kliewer et al., 2002). PXR activation regulates the expression of xenobiotics oxidation and conjugation enzymes, and transporters, involved in the metabolism and elimination of potentially harmful chemicals from the body. Previous studies revealed CYP3A4 induction by RIFax in a human hepatocyte model. Two clinical studies that used MDZ and an oral contraceptive containing ethinyl estradiol and norgestimate (Trapnell et al., 2007) demonstrated that RIFax did not alter the pharmacokinetics of these drugs, indicating that RIFax had no significant effect on intestinal or hepatic CYP3A4 (http://www.salix.com/). However, in the current study, intestinal CYP3A11 was significantly up-regulated in hPXR mice treated with RIFax. In the pharmacokinetics study of MDZ in hPXR mice pretreated with RIFax, a 20% decrease of Cmax was observed that was consistent with the Cmax increase of its major metabolite 1'-OHMDZ, and it can be explained by the first-pass effect through intestinal CYP3A metabolism. However, there was no parallel decrease of MDZ AUC in hPXR mice pretreated with RIFax. AUC is not only related to first-pass elimination but also to other factors, such as absorption. In hPXR mice pretreated with RIFax, several intestinal genes including transporters were up-regulated, such as the influx transporter OATP2, which may contribute to the increase of MDZ absorption. A bioavailability study on MDZ was not performed because of its poor bioavailability and large variation in mice (Granvil et al., 2003). Overall, RIFax-mediated intestinal CYP3A induction and potential drug-drug interactions should be reassessed in future studies because of intestinal first-pass effects (Doherty and Charman, 2002; Granvil et al., 2003).
The beneficial aspects of PXR activation is its role in detoxication by up-regulating the enzymes and transporters involved in elimination of the xenobiotics, including cytochromes P450, GST, OATP, and MRP (Kliewer, 2003; Saini et al., 2005; Wagner et al., 2005). PXR target genes are critical components in intestinal barrier function against xenobiotics and bacteria (Langmann et al., 2004). In the small intestine of hPXR mice treated with RIFax, several PXR target genes such as CYP3A11, GSTA1, MRP2, and OATP2 were up-regulated. The contribution of RIFax-mediated PXR activation as a mechanism for the effects of the drug on chronic gastrointestinal disorders should be considered. Clinically, RIFax was found to be beneficial in the treatment of multiple chronic gastrointestinal disorders, such as hepatic encephalopathy, intestinal gas and gas-related symptoms, diverticular disease, pouchitis, and IBD (Scarpignato and Pelosini, 2005). The mechanisms contributing to the beneficial effects of RIFax in chronic gastrointestinal disorders are not fully understood, and they cannot be explained simply as RIFax antibiotic activity. Recent studies revealed that the susceptibility to IBD was strongly associated with the genetic variation in the PXR gene, and several PXR genes were dysregulated or down-regulated in both ulcerative colitis and Crohn's disease patients (Langmann et al., 2004; Dring et al., 2006). In a DSS-induced IBD mouse model, PCN-mediated PXR activation significantly prevented DSS-induced colitis (Shah et al., 2007), which indicates the potential value of PXR ligands as a therapeutic for IBD. Further human studies are suggested to assess the role of RIFax-mediated gut PXR activation in therapeutics of chronic gastrointestinal disorders.
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Acknowledgements |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: RIFax, rifaximin, 4-deoxy-4'-methylpyrido[1',2'-1,2]imidazo[5,4-c]rifamycin SV; CD, Crohn's disease; IBD, inflammatory bowel disease; PXR, pregnane X receptor; DSS, dextran sulfate sodium; PCN, pregnenolone 16-carbonitrile; RIF, rifampicin, 3-(4-methylpiperazinyliminomethyl)rifamycin SV; hPXR, PXR-humanized; MDZ, midazolam; 1'-OH-MDZ, 1'-hydroxymidazolam; WT, wild-type; AUC, area under the serum concentration-time curve; LC-MS/MS, liquid chromatography-tandem mass spectrometry; qPCR, quantitative real-time polymerase chain reaction; GSTA, glutathione S-transferase ; MRP, multidrug resistance protein; OATP, organic anion transporting polypeptide; CAR, constitutive androstane receptor; PPAR, peroxisome proliferator-activated receptor; FXR, farnesoid X receptor; DMSO, dimethyl sulfoxide; Wy-14,643, pirinixic acid, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid; WT, wild-type mice; Fwd, forward; Rev, reverse; S. intestine, small intestine; GW4064, 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic.
Address correspondence to: Dr. Frank J. Gonzalez, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bldg. 37, Room 3106, Bethesda, MD 20892. E-mail: fjgonz{at}helix.nih.gov
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