Experimental studies on clinical application of 13N-ammonia; clinical application of the functional image

1) Clinical application: Dynamic scintigraphy of liver and heart of a patient having liver cirrhosis after intrasigmoidal administration of 13N-ammonia (pH 8.1) were performed. Simultaneously, continuous measurments of radioactivity at the left side abdomen and the left temporal region were done by using a scintillation detector for renography. Successive measurement of radioactivity of blood was also carried out. 2) Comstruction of functional images of liver and heart: By using digital radioisotope image of liver and heart of the patient after intrasigmoidal administration of 13N-ammonia, the maps with respect to parameters described in the pervious paper were constructed.     

Results of L-[1-13C]phenylalanine breath test with air isotope ratio mass spectrometry can reflect the activity of phenylalanine hydroxylase in cirrhotic rat liver

The L-[1-13C]phenylalanine breath test (PheBT) could potentially advance the evaluation of hepatocyte function and liver functional reserve. However, because the factors influencing PheBT results have not been clarified, the clinical application of the test has been limited. This study investigated the relationship between the parameters of PheBT, performed with air isotope ratio mass spectrometry, and the activity of phenylalanine hydroxylase (PAH), the phenylalanine metabolism rate-limiting enzyme, in rat liver, and proposes valid parameters for the assessment of liver function. Chronic injury to the liver was induced by the administration of CCl4 to male Sprague-Dawley rats for either 8 or 12 weeks. Livers from rats in the two cirrhotic groups were discolored, enlarged and roughly textured, with cells filled with fat granules of various sizes, pseudolobuli formations, and regenerated tubercles. Of the 12 parameters tested, only the unit liver weight (LW) breath test parameters, including the maximum abundance of 13C in breath (13Cmax/LW), 13C abundance in breaths 2 and 7 min after administration of L-[1-(13)C]phenylalanine (13C-phe) (13C2/LW and 13C7/LW), cumulative 13C excretion 10 and 30 min after 13C-phe administration (AUC10/LW and AUC30/LW), and the 13C excretion rate constant (PheBT-k/LW) were significantly affected in the chronic liver injury groups. There was no significant difference in the total PAH activity in liver among the three groups, but there was significant difference in unit LW PAH activity. Total PAH activity in the liver was significantly correlated with 13Cmax, 13C2, 13C7, AUC10, AUC30 and PheBT-k, while the unit LW PAH activity was significantly correlated with 13Cmax/LW, 13C2/LW, 13C7/LW, AUC10/LW, AUC30/LW and PheBT-k/LW. PheBT-k/LW was also correlated with biochemical indices that are used to assess liver function. The present findings indicate that the PheBT results based on air isotope ratio mass spectrometry can quantitatively reflect the change in total PAH activity in the livers of chronically injured rats. PheBT-k and PheBT-k/LW are the most sensitive among the test parameters, and can be used to assess liver functional reserve and hepatocyte damage at the molecular level.     

Evaluation of 13C-phenylalanine and 13C-tyrosine breath tests for the measurement of hepatocyte functional capacity in patients with liver cirrhosis.

Liver disease is associated with an abnormal elevation of the plasma concentrations of the aromatic amino acids phenylalanine and tyrosine. The liver is the main site of aromatic amino acid metabolism, particularly the hydroxylation of phenylalanine to tyrosine and further tyrosine degradation. In the present study, we have examined the usefulness of the L-[1-13C]phenylalanine breath test (13C-PheBT) and L-[13C]tyrosine breath test (13C-TyrBT) for the detection of hepatic damage in patients with liver cirrhosis. First, the time courses of 13CO2 excretion after the administration of L-[1-13C]phenylalanine and L-[1-13C]tyrosine were compared. The peak times (the time expressed in minutes at which 13CO2 excretion was maximal) were 20 min in both breath tests, but 13C-TyrBT gave a higher peak than 13C-PheBT. Next, the parameters of 13C-PheBT and 13C-TyrBT were compared with biochemical liver function test values. These parameters were well correlated with several liver blood test values conventionally regarded as measures of hepatocyte functional reserve. Therefore, 13C-PheBT and 13C-TyrBT may be useful to assess the degree and progression of hepatic dysfunction.     

Strategic identification of in vitro metabolites of 13-desmethyl spirolide C using liquid chromatography/high-resolution mass spectrometry

A strategy to identify metabolites of a marine biotoxin, 13-desmethyl spirolide C, has been developed using liquid chromatography coupled to high-resolution mass spectrometry (LC/HRMS). Metabolites were generated in vitro through incubation with human liver microsomes. A list of metabolites was established by selecting precursor ions of a common fragment ion characteristic of the spirolide toxin which was known to contain a cyclic imine ring. Accurate mass measurements were subsequently used to confirm the molecular formula of each biotransformation product. Using this approach, a total of nine phase I metabolites was successfully identified with deviations of mass accuracy less than 2 ppm. The biotransformations observed included hydroxylation, dihydroxylation, oxidation of a quaternary methyl group to hydroxymethyl or carboxylic acid groups, dehydrogenation and hydroxylation, as well as demethylation and dihydroxylation reactions. In a second step, tandem mass spectrometry (MS/MS) was performed to elucidate structures of the metabolites. Using the unique fragment ions in the spectra, the structures of the three major metabolites, 13,19-didesmethyl-19-carboxy spirolide C, 13,19-didesmethyl-19-hydroxymethyl spirolide C and 13-desmethyl-17-hydroxy spirolide C, were assigned. Levels of 13-desmethyl spirolide C and its metabolites were monitored at selected time points over a 32-h incubation period with human liver microsomes. It was determined that 13,19-didesmethyl-19-carboxy spirolide C became the predominant metabolite after 2 h of incubation. The stability plot of 13-desmethyl spirolide C showed first-order kinetics for its metabolism and the intrinsic clearance was calculated to be 41 μL/min/mg, suggesting first-pass metabolism may contribute to limiting oral toxicity of 13-desmethyl spirolide C.     

Induction of Liver Size Reduction in Zebrafish Larvae by the Emerging Synthetic Cannabinoid 4F-MDMB-BINACA and Its Impact on Drug Metabolism

Zebrafish (ZF; Danio rerio) larvae have become a popular in vivo model in drug metabolism studies. Here, we investigated the metabolism of methyl 2-[1-(4-fluorobutyl)-1H-indazole-3-carboxamido]-3,3-dimethylbutanoate (4F-MDMB-BINACA) in ZF larvae after direct administration of the cannabinoid via microinjection, and we visualized the spatial distributions of the parent compound and its metabolites by mass spectrometry imaging (MSI). Furthermore, using genetically modified ZF larvae, the role of cannabinoid receptor type 1 (CB1) and type 2 (CB2) on drug metabolism was studied. Receptor-deficient ZF mutant larvae were created using morpholino oligonucleotides (MOs), and CB2-deficiency had a critical impact on liver development of ZF larva, leading to a significant reduction of liver size. A similar phenotype was observed when treating wild-type ZF larvae with 4F-MDMB-BINACA. Thus, we reasoned that the cannabinoid-induced impaired liver development might also influence its metabolic function. Studying the metabolism of two synthetic cannabinoids, 4F-MDMB-BINACA and methyl 2-(1-(5-fluoropentyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxamido)-3,3-dimethylbutanoate (7′N-5F-ADB), revealed important insights into the in vivo metabolism of these compounds and the role of cannabinoid receptor binding.     

Interaction of surface-active drugs in rabbits

The interaction of chlorpromazine and promethazine in vivo has been investigated. The drugs were administered to the rabbit orally as a single dose (100 mg of each drug) as well as simultaneously with an interval of 15 min. The presence of multiple peaks at the separate administration of promethazine and chlorpromazine on the one hand, and increase of number of peaks, symbathic character of kinetic curves of mentioned drugs and its prolonged appearance in the systemic circulation of the blood by simultaneous administration on the other hand, may be explained by the intensive presystem metabolism and surface-activity ability of these drugs, and by the periodic 'lassitude' of liver for their capture and elimination (either presystem or systemic). The micelle formation from these drugs in the gastro-intestinal tract and formation of the mixed micelles on simultaneous administration were also taken into consideration. Chlorpromazine is more strongly captured by the liver at its first pass through it than promethazine, from comparison of pharmacokinetics of these drugs administered separately. Therefore, chlorpromazine on simultaneous administration occupies the sites of the liver which were covered by promethazine at single dose, thereby substituting promethazine and promoting its transferral into the systemic blood circulation. This results in a large increase in promethazine content in blood, additional peaks appear and the presence of promethazine in the blood is prolonged. The influence of chlorpromazine on the kinetics of promethazine is especially obvious when chlorpromazine enters the organism first and more easily occupies those sites in the liver which participate in the capture and elimination of both drugs. Concerning influence of promethazine on the kinetics of chlorpromazine, promethazine reinforces in some way the ability of liver to capture chlorpromazine, thereby intensifying the presystem metabolism of chlorpromazine and inhibiting its own metabolism. The analogous effect was observed in the study of the influence of promethazine on the kinetics of carbamazepine.     

In vivo and in vitro metabolism of a novel β2-adrenoceptor agonist, trantinterol: metabolites isolation and identification by LC-MS/MS and NMR

Trantinterol is a novel β₂-adrenoceptor agonist used for the treatment of asthma. The aim of this study is to identify the metabolites of trantinterol using liquid chromatography tandem mass spectrometry (LC-MS/MS), to isolate the main metabolites, and confirm their structures by nuclear magnetic resonance (NMR). Urine, feces, bile, and blood samples of rats were obtained and analyzed. Reference standards of six metabolites were achieved with the combination of chemical synthesis, microbial transformation, and the model systems of rats. Moreover, in order to investigate the phase I metabolism of trantinterol in humans and to study the species differences between rats and humans, incubations with liver microsomes were performed. The biotransformation by a microbial model Cunninghamella blakesleana AS 3.970 was also studied. A total of 18 metabolites were identified in vivo and in vitro together, 13 of which were newly detected. Three phase I metabolites were detected in vivo and in vitro as well as in the microbial model, including the arylhydroxylamine (M1), the tert-butyl hydroxylated trantinterol (M2) and the 1-carbonyltrantinterol (M3). Another important pathway in rats is glutathione conjugation and further catabolism and oxidation to form consecutive derivatives (M4 through M10). Other metabolites include glucuronide, glucoside, and sulfate conjugates. The results of in vitro experiments indicate no species difference exists among rats, humans, and C. blakesleana AS 3.970 on the phase I metabolism of trantinterol. Our study provided the most comprehensive picture for trantinterol in vivo and in vitro metabolism to this day, and may predict its metabolism in humans.     

Metabolism of methylstenbolone studied with human liver microsomes and the uPA+/+‐SCID chimeric mouse model

Anti‐doping laboratories need to be aware of evolutions on the steroid market and elucidate steroid metabolism to identify markers of misuse. Owing to ethical considerations, in vivo and in vitro models are preferred to human excretion for nonpharmaceutical grade substances. In this study the chimeric mouse model and human liver microsomes (HLM) were used to elucidate the phase I metabolism of a new steroid product containing, according to the label, methylstenbolone. Analysis revealed the presence of both methylstenbolone and methasterone, a structurally closely related steroid. Via HPLC fraction collection, methylstenbolone was isolated and studied with both models. Using HLM, 10 mono‐hydroxylated derivatives (U1–U10) and a still unidentified derivative of methylstenbolone (U13) were detected. In chimeric mouse urine only di‐hydroxylated metabolites (U11–U12) were identified. Although closely related, neither methasterone nor its metabolites were detected after administration of isolated methylstenbolone. Administration of the steroid product resulted mainly in the detection of methasterone metabolites, which were similar to those already described in the literature. Methylstenbolone metabolites previously described were not detected. A GC‐MS/MS multiple reaction monitoring method was developed to detect methylstenbolone misuse. In one out of three samples, previously tested positive for methasterone, methylstenbolone and U13 were additionally detected, indicating the applicability of the method. Copyright © 2014 John Wiley & Sons, Ltd.     

Excess electrons bound to small ammonia clusters

Dipole-bound anions of small water clusters (H2O) N- (N >or= 2) are well-known from experiment and theory. In contrast, the smallest ammonia cluster anion detected so far is the 13-mer (NH3)13-. Here dipole-bound states of small ammonia clusters (NH3)N- (N = 2, 3, 4) are investigated using coupled-cluster ab initio methods. The trimer is found to be the smallest ammonia cluster able to form a dipole bound state, and its vertical detachment energy is predicted to be 27 meV, somewhat smaller than that of the water dimer. For the ammonia tetramer dipole-bound states with triple-acceptor monmers are identified akin to the well-studied double-acceptor binding motif of water cluster anions. Moreover, a (NH3)6-)hexamer that has been considered as a model for a cavity-bound state is examined. Ab initio results for this system challenge the notion that an electron localized in an ammonia cavity can be thought of as a delocalized radical anion.     

Effect of water extracts of aloe and some herbs in decreasing blood ethanol concentration in rats. II

Oral administration of ethanol to rats at a dose of 3 g/kg decreased alcohol dehydrogenase (ADH) activity and metabolism of lactate to pyruvate in the liver. The effects of water extracts of Aloe and some other herbs on blood ethanol concentration and on ADH activity in liver cytosol were examined. The water extracts of these herbs caused a faster elimination of ethanol from blood of normal rats when administered orally 30 min before oral administration of ethanol. The rapid elimination of ethanol seems to be due to a protection of ADH activity and the supply of nicotinamide dinucleotide, both of which are reduced by high ethanol concentration. The effects of ethanol in decreasing the enzyme activities relating to its own metabolism occur when high concentrations of ethanol pass through the liver, and thus may primarily appear during the absorption of alcohol from the gastrointestinal tract, when portal concentration of ethanol are very high.     

Screening for in vivo metabolites of isovalertatin family oligosaccharides in rats by liquid chromatography coupled to electrospray ionization tandem mass spectrometry

Liquid chromatography/electrospray ionization tandem mass spectrometry (LC/MS(n)) was used to identify trace levels of in vivo metabolites after the administration of isovalertatin M23 or isovalertatin D23 to rats. The biosamples of urine, feces, and ileum incubation were pre-treated by solid-phase extraction (SPE), and then chromatographed with a reversed-phase C8 column with acetonitrile/1.5 mM aqueous ammonia (18:82, v/v) as the mobile solvent. The parent drug and the possible metabolites were identified by two independent qualitative parameters, retention time and collision-induced dissociation product ions. Nine and seven metabolites were successfully characterized from biosamples after administration of isovalertatins M23 and D23, respectively, to rats. The metabolism seemed to take place in the rat intestinal tract, and metabolic pathways were identified including isovaleryl de-esterification and hydrolysis of alpha-glucose units located either at the reducing or the non-reducing terminus.     

Microdetermination of glucose content of plasma and its isotopic enrichment using capillary gas chromatography/ammonia chemical-ionization mass spectrometry

A new sensitive and precise method for the determination of the isotopic enrichment of [6,6-D2]glucose and concentration of glucose in plasma microsamples (20 microL) has been developed. Glucose was extracted from plasma samples by anion-cation column-exchange with absolute ethanol, derivatized as 1,2:3,5-bis(butylboronate)-6-acetyl-alpha-D-glucofuranose, and analysed by capillary gas chromatography/ammonia chemical-ionization mass spectrometry. This method gives a better reproducibility and precision (variation coefficient below 1%) than methods using isobutane chemical ionization. Stable isotopes are being used increasingly to investigate energy metabolism in vivo. Recent work has involved the development of methodologies, especially mass spectrometry, to perform tracer experiments using the stable isotopes 3H, 13C, or 13N(1-4). Chemical-ionization mass spectrometry is extensively used for the analysis of isotopically labelled amino acids. In neonates and children, "true" glucose production can be measured by the continuous infusion of the stable isotopically labelled tracer 6,6-dideutero-glucose (6,6-D2-glucose), and analytical measurement is performed using gas chromatography/electron-ionization mass spectrometry (GC/EIMS). Herein, we present a new, simple and sensitive method for the determination of the isotopic enrichment of [6,6-D2]glucose and measurement of the concentration of glucose in plasma microsamples (20 microL), based on the use of capillary gas-chromatography/ammonia chemical-ionization mass spectrometry of 1,2:3,5-bis(butylboronate)-6-acetyl-alpha-D-glucofuranose.     

Interaction of carbamazepine and chlorpromazine in rabbits.

The interaction of carbamazepine and chlorpromazine in rabbits has been studied. The drugs were administrated as single oral doses (200 mg of each drug). The sequence of administration of the drugs was varied. It has been established that by simultaneous administration these drugs decrease absorption of each other in plasma. This may be explained by competition of the drugs to transfer from the gastrointestinal tract into plasma, as well as by the formation of complexes, more or less stable and more or less bound to gastrointestinal tissues. Carbamazepine intensifies the biotransformation of chlorpromazine, which may be caused by the ability of carbamazepine to induce microsomal liver enzymes. Chlorpromazine suppresses the biotransformation of carbamazepine, however. This may be caused by intensive capture of chlorpromazine by liver tissues and by its intensive biotransformation, which in turn is conditioned by its surface-active nature and by the increase of its metabolism with carbamazepine. Therefore the biotransformation of chlorpromazine is increased and metabolism of carbamazepine is reduced. The sequence of administration of the drugs affects their pharmacokinetics significantly.     

Development of a molecular dynamics-based coalescence model for DSMC simulations of ammonia condensate flows

A coalescence model for homogeneous condensation of ammonia in supersonic expansions to vacuum has been developed using molecular dynamics trajectory calculations. The MD calculations show that the sticking probability increases as the ammonia cluster size increases or the cluster temperature decreases. In addition, the sensitivity of the sticking probability to cluster size decreases as the temperature decreases. Comparison of the Ashgriz-Poo semiempirical coalescence model with MD simulations show that for cluster sizes larger than 100 the former model may be used. To model homogeneous nucleation in an ammonia jet, direct simulation Monte Carlo (DSMC) simulations were performed for different stagnation pressure conditions using the MD simulation outcomes for smaller cluster-cluster collisions and the Ashgriz-Poo model for cluster sizes larger than 100. We found that, by including the combined coalescence model, the average cluster sizes and size distributions predicted by DSMC agree reasonably well with experiment.     

绿卡色林衍生物的合成、体外代谢及体内活性研究

将选择性5-HT2C受体激动剂类减肥药绿卡色林分子中的仲胺转化成氨基甲酸酯类前药,设计合成了13个氨基甲酸酯类化合物.新化合物的结构经核磁共振波谱、红外光谱及高分辨质谱确证.通过体外代谢稳定性实验,筛选出半衰期长且可通过代谢持续产生绿卡色林的新化合物6b.对化合物6b的大鼠减肥药理实验结果表明,在日剂量相同的条件下,化合物6b给药1次/d比绿卡色林给药2次/d的减肥效果略好.     

Surface-deposited acid/base on glass microfibers in formation of (3-aminopropyl)triethoxysilane-[2-(3,4-epoxycyclohexyl)ethyl]heptaisobutyloctasilsesquioxane bioverlay

Silanization of macroporous glass microfiber filters with (3-aminopropyl)triethoxysilane (APTES) and subsequent binding of [2-(3,4-epoxycyclohexyl)ethyl]heptaisobutyloctasilsesquioxane (E-POSS) to the amine-terminated surface of microfibers was studied. Prior to the silanization, minute quantities of concentrated aqueous solutions of hydrochloric acid or ammonia were adsorbed in the filters while attachment of E-POSS molecules to APTES overlay was not specially catalyzed. Analysis of DRIFT, XPS, and 13C CP/MAS NMR spectra has shown that the formation of APTES overlay is affected differently by the surface-deposited acid or base. It was proved by XPS that microfibers with the adsorbed acid take up higher amounts of covalently attached APTES by 42% and, subsequently, of E-POSS by 65% than microfibers with the adsorbed ammonia. The molecular mechanics model calculations, which were made using silica as a template, have shown that approximately two-layered APTES coating can be built on the model surface if complete hydrolysis of ethoxy groups and vertical condensation of APTES species are assumed.     

Metabolic alterations in triptolide‐induced acute hepatotoxicity

Triptolide, a major active constitute of Tripterygium wilfordii Hook. F, is prescribed for the treatment of autoimmune diseases in China. One of its most severe adverse effects observed in the clinical use is hepatotoxicity, but the mechanism is still unknown. Therefore, the present study applied an LC/MS‐based metabolomic analysis to characterize the metabolomic changes in serum and liver induced by triptolide in mice. Mice were administered triptolide by gavage to establish the acute liver injury model, and serum biochemical and liver histological analyses were applied to assess the degree of toxicity. Multivariate data analyses were performed to investigate the metabolic alterations. Potential metabolites were identified using variable importance in the projection values and Student's t‐test. A total of 30 metabolites were observed that were significantly changed by triptolide treatment and the abundance of 29 metabolites was correlated with the severity of toxicity. Pathway analysis indicated that the mechanism of triptolide‐induced hepatotoxicity was related to alterations in multiple metabolic pathways, including glutathione metabolism, tricarboxylic acid cycle, purine metabolism, glycerophospholipid metabolism, taurine and hypotaurine metabolism, pantothenate and CoA biosynthesis, pyrimidine metabolism and amino acid metabolism. The current study provides new mechanistic insights into the metabolic alterations that lead to triptolide‐induced hepatotoxicity.     

Hepatoprotective Effects of Ixeris chinensis on Nonalcoholic Fatty Liver Disease Induced by High-Fat Diet in Mice: An Integrated Gut Microbiota and Metabolomic Analysis

Ixeris chinensis (Thunb.) Nakai (IC) is a folk medicinal herb used in Mongolian medical clinics for the treatment of hepatitis and fatty liver diseases even though its pharmacological mechanism has not been well characterized. This study investigated the hepatoprotective mechanism of IC on mice with nonalcoholic fatty liver disease (NAFLD) by integrating gut microbiota and metabolomic analysis. A high-fat diet (HFD) was used to develop nonalcoholic fatty liver disease, after which the mice were treated with oral IC (0.5, 1.5 and 3.0 g/kg) for 10 weeks. HFD induced NAFLD and the therapeutic effects were characterized by pathological and histological evaluations, and the serum indicators were analyzed by ELISA. The gut microbial and metabolite profiles were studied by 16S rRNA sequencing and untargeted metabolomic analysis, respectively. The results showed that the administration of IC resulted in significant decreases in body weight; liver index; serum biomarkers such as ALT, TG, and LDL-C; and the liver inflammatory factors IL-1β, IL-6, and TNF-α. The 16S rRNA sequencing results showed that administration of IC extract altered both the composition and abundance of the gut microbiota. Untargeted metabolomic analysis of liver samples detected a total of 212 metabolites, of which 128 were differentially expressed between the HFD and IC group. IC was found to significantly alter the levels of metabolites such as L-glutamic acid, pyridoxal, ornithine, L-aspartic acid, D-proline, and N4-acetylaminobutanal, which are involved in the regulation of glutamine and glutamate, Vitamin B6 metabolism, and arginine and proline metabolic pathways. Correlation analysis indicated that the effects of the IC extract on metabolites were associated with alterations in the abundance of Akkermansiaceae, Lachnospiraceae, and Muribaculaceae. Our study revealed that IC has a potential hepatoprotective effect in NAFLD and that its function might be linked to improvements in the composition of gut microbiota and their metabolites.     

Catalytic ammonia oxidation on platinum: mechanism and catalyst restructuring at high and low pressure

Catalytic ammonia oxidation over platinum has been studied experimentally from UHV up to atmospheric pressure with polycrystalline Pt and with the Pt single crystal orientations (533), (443), (865), and (100). Density functional theory (DFT) calculations explored the reaction pathways on Pt(111) and Pt(211). It was shown, both in theory and experimentally, that ammonia is activated by adsorbed oxygen, i.e. by O(ad) or by OH(ad). In situ XPS up to 1 mbar showed the existence of NH(x)(x= 0,1,2,3) intermediates on Pt(533). Based on a mechanism of ammonia activation via the interaction with O(ad)/OH(ad) a detailed and a simplified mathematical model were formulated which reproduced the experimental data semiquantitatively. From transient experiments in vacuum performed in a transient analysis of products (TAP) reactor it was concluded that N(2)O is formed by recombination of two NO(ad) species and by a reaction between NO(ad) and NH(x,ad)(x= 0,1,2) fragments. Reaction-induced morphological changes were studied with polycrystalline Pt in the mbar range and with stepped Pt single crystals as model systems in the range 10(-5)-10(-1) mbar.     

Serum metabonomics characterization of liver fibrosis induced by bile duct-ligated in rats and the intervention effects of herb compound 861

Liver fibrosis has been increasingly recognized as a cause for high morbidity and mortality of some diseases in humans. Herbal medicines have received great attention due to their low side effects and high safety. Herbal compound 861 (Cpd 861) has been effectively used for treating hepatic fibrosis for long time. Yet, its exact mechanism is still in fancy. Herein, we first established a liver fibrosis model by bile duct ligation (BDL), which led to the toxic accumulation of bile acids in animals, resulting in hepatic fibrosis. A serum metabonomics study on BDL-induced liver fibrosis rats after Cpd 861 treatment was performed using UHPLC-QTOF/MS. Multivariate analysis showed that Cpd 861 significantly reversed the metabolic perturbation induced by BDL to normal state, which is in agreement with the serum biochemical and histopathological findings. 15 metabolites were screened as potential biomarkers. Eight metabolic pathways were recognized as the most relevant pathways, involving dysfunction of amino acids metabolism and synthesis, fatty acid metabolism, phospholipids metabolism, and others. This is the first study to reveal the underlying mechanism of Cpd 861 based on metabonomics, which is complementary to biochemical analysis, and more importantly, a potentially powerful tool to interpret the mechanisms of extremely complex systems.