Importance of Considering Fed-State Gastrointestinal Physiology in Predicting the Reabsorption of Enterohepatic Circulation of Drugs.

PURPOSE: The purpose of this study was to develop a simulation model for the pharmacokinetics (PK) of drugs undergoing enterohepatic circulation (EHC) with consideration to the environment in the gastrointestinal tract in the fed state in humans. The investigation particularly focused on the necessity of compensating for the permeability rate constant in the reabsorption process in consideration of drug entrapment in bile micelles. METHODS: Meloxicam and ezetimibe were used as model drugs. The extent of the entrapment of drugs inside bile micelles was evaluated using the solubility ratio of Fed State Simulated Intestinal Fluid version 2 (FeSSIF-V2) to Fasted State Simulated Intestinal Fluid version 2 (FaSSIF-V2). Prediction accuracy was evaluated using the Mean Absolute Percentage Error (MAPE) value, calculated from the observed and predicted oral PK profiles. RESULTS: The solubilization of ezetimibe by bile micelles was clearly observed while that of meloxicam was not. Assuming that only drugs in the free fraction of micelles permeate through the intestinal membrane, PK simulation for ezetimibe was performed in both scenarios with and without compensation by the permeation rate constant. The MAPE value of Zetia® tablet, containing ezetimibe, was lower with compensation than without compensation. By contrast, Mobic® tablet, containing meloxicam, showed a relatively low MAPE value even without compensation. CONCLUSION: For drugs which undergo EHC and can be solubilized by bile micelles, compensating for the permeation rate constant in the reabsorption process based on the free fraction ratio appears an important factor in increasing the accuracy of PK profile prediction.

Effects of interrupting the enterohepatic circulation in amatoxin intoxications.

BACKGROUND: Interruption of the enterohepatic circulation is regarded as an effective way to treat patients with amatoxin poisoning. Nonetheless, its effectiveness has not yet been systematically evaluated. Therefore, we performed a systematic review to investigate the role of enterohepatic circulation on patient outcome and clinical laboratory values. We specifically sought to evaluate the effect of activated charcoal, which absorbs drugs and toxins in the gastrointestinal tract. METHODS: A previously established database with data extracted from case reports and series from literature, supplemented with recent publications, was used. Patient characteristics, outcome, and laboratory values were evaluated. RESULTS: We included 133 publications describing a total of 1,119 unique cases. Survival was 75 per cent in the control group (n = 452), whereas in the group treated with single or multiple doses of activated charcoal (n = 667) survival was 83 per cent (P < 0.001, odds ratio 1.89 [95 per cent confidence interval 1.40-2.56]). Furthermore, no difference in peak values of alanine aminotransferase and aspartate aminotransferase activities were observed, whereas peak values of total serum bilirubin concentration and international normalized ratio were statistically significantly reduced in patients treated with activated charcoal. DISCUSSION: The ability of activated charcoal to enhance the elimination of amatoxin through interruption of the enterohepatic circulation offers a potentially safe and inexpensive therapy for patients in the post-absorptive phase. LIMITATIONS: Limitations include the potential for publication bias, the lack of universal confirmation of amatoxin concentrations, and the inability to directly measure enterohepatic circulation of amatoxin. CONCLUSION: Treatment with activated charcoal in patients with amatoxin poisoning was associated with a greater chance of a successful outcome. Additionally, activated charcoal was associated with a reduction in markers of liver function, but not markers of liver injury.

Lactobacillus fermentum MCC2760 abrogate high-fat induced perturbations in the enterohepatic circulation of bile acids in rats.

AIM: This study in hyperlipidemic rats elucidated the effect of Lactobacillus fermentum MCC2760 on intestinal bile acid (BA) uptake, hepatic BA synthesis, and enterohepatic BA transporters. MAIN METHODS: Diets rich in saturated fatty acids [coconut oil (CO)] and omega-6 fatty acids [sunflower oil (SFO)] at 25 g fat/100 g diet were fed to rats with or without MCC2760 (109 cells/kg body weight). After 60 days of feeding, intestinal BA uptake and expression of Asbt, Osta/b mRNA and protein, and hepatic expression of Ntcp, Bsep, Cyp7a1, Fxr, Shp, Lrh-1, and Hnf4a mRNA were measured. Hepatic expression of HMG-CoA reductase protein and its activity and total BAs in serum, liver, and feces were assessed. KEY FINDINGS: Hyperlipidaemic groups (HF-CO and HF-SFO) had: 1) increased intestinal BA uptake, Asbt and Osta/b mRNA expression, and ASBT staining 2) increased BA in serum, 3) decreased hepatic expression of Ntcp, Bsep, and Cyp7a1 mRNA, and NTCP staining 4) increased activity of HMG-CoA reductase, 5) increased hepatic expression of Fxr and Shp mRNA, 6) decreased hepatic expression of Lrh-1 and Hnf4a mRNA, and 7) decreased BA in Feces when compared to their respective controls (N-CO and N-SFO) and experimental groups (HF-CO + LF and HF-SFO + LF). Immunostaining revealed increased intestinal Asbt and hepatic Ntcp protein expression in the HF-CO and HF-SFO groups compared to control and experimental groups. SIGNIFICANCE: Incorporating probiotics like MCC2760 abrogated hyperlipidemia-induced changes in the intestinal uptake, hepatic synthesis, and enterohepatic transporters of BA in rats. Probiotic MCC2760 can be used to modulate lipid metabolism in high-fat-induced hyperlipidemic conditions.

Disruption of Enterohepatic Circulation of Bile Acids Ameliorates Small Bowel Resection Associated Hepatic Injury.

BACKGROUND: Massive small bowel resection (SBR) is associated with liver injury and fibrosis. Efforts to elucidate the driving force behind hepatic injury have identified multiple factors, including the generation of toxic bile acid metabolites. METHODS: Sham, 50% proximal, and 50% distal SBR were carried out in C57BL/6 mice to determine the effect of jejunal (proximal SBR) versus ileocecal resection (distal SBR) on bile acid metabolism and liver injury. Tissues were harvested at 2 and 10-week postoperative timepoints. RESULTS: When compared with 50% proximal SBR, mice that underwent distal SBR exhibited less hepatic oxidative stress as verified by decreased mRNA expression of tumor necrosis factor-α (TNFα, p ≤ 0.0001), nicotinamide adenine dinucleotide phosphate oxidase (NOX, p ≤ 0.0001), and glutathione synthetase (GSS, p ≤ 0.05). Distal SBR mice also exhibited a more hydrophilic bile acid profile with reduced abundance of insoluble bile acids (cholic acid (CA), taurodeoxycholic acid (TCA), and taurolithocholic acid (TLCA)), and increased abundance of soluble bile acids (tauroursodeoxycholic acid (TUDCA)). In contrast with proximal SBR, ileocecal resection alters enterohepatic circulation leading to reduced oxidative stress and promotes physiological bile acid metabolism. CONCLUSION: These findings challenge the notion that preservation of the ileocecal region is beneficial in patients with short bowel syndrome. Administration of selected bile acids may present potential therapy to mitigate resection-associated liver injury. LEVEL OF EVIDENCE: III-Case-Control Study.

[Evaluation and Clarification of Enterohepatic Interactions in Pharmacokinetics].

The evaluation and prediction of pharmacokinetics in humans is important in the field of drug discovery and development. Generally, human pharmacokinetics is predicted using physiologically based pharmacokinetic models that include physiological and physicochemical (drug) parameters obtained from in vitro assays. Specific organ dysfunction, such as liver disease, also affects the functions of other organs, causing unexpected pharmacokinetic fluctuations. I investigated the effect of cholestasis on intestinal drug absorption in mice subjected to bile duct ligation (BDL). The intestinal absorption and permeability of imatinib was decreased in BDL mice compared with sham-operated mice, and this may be attributed to the up-regulation of the efflux transporter, breast cancer resistance protein. However, a single-organ experimental system cannot predict such pharmacokinetic changes. To overcome this challenge, I investigated a microphysiological system (MPS) equipped with intestinal and hepatic cells for pharmacokinetic evaluation. The glucuronidation of triazolam was significantly increased in an enterohepatic MPS compared with a single-culture system. These results suggested that the elucidation of organ interactions requires the use of an MPS loaded with human cells in combination with laboratory animal studies. In this review, I present the results of my evaluation of organ interactions using animal models and MPSs in the Award for Young Scientists from the Pharmaceutical Society of Japan, Hokuriku Branch.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor.

OBJECTIVE: This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR). METHODS: Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway. RESULTS: Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon. CONCLUSION: Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Influence of Calcineurin Inhibitors and Genetic Polymorphism of Transporters on Enterohepatic Circulation and Exposure of Mycophenolic Acid in Chinese Adult Renal Allograft Recipients.

There is significant enterohepatic circulation (EHC) during the disposition of mycophenolic acid (MPA). The aim of this study was to elucidate factors influencing the EHC of MPA in Chinese adult renal allograft recipients. After 2 weeks of therapy with mycophenolate mofetil or enteric-coated mycophenolate sodium, blood samples were collected from 125 patients at 0 to 12 hours post-administration and MPA concentrations were determined. The influence of calcineurin inhibitors (CNIs) and genetic polymorphisms on MPA exposure and EHC was studied. The Shapley additive explanations method was used to estimate the impact of various factors on the area under the plasma drug concentration-time curve (AUC0-12h ) for MPA. An extreme gradient boosting (XGboost) machine learning-based model was established to predict AUC0-12h . Results showed that the dose-normalized AUC6-12h (dn-AUC6-12h ) of MPA was significantly lower in patients co-administered with cyclosporine (CsA) than in patients co-administered with tacrolimus (TAC) (P < .05). For patients co-administered with TAC, patients with ABCC2 C-24T CC or SLCO1B1 T521C TT genotypes had significantly higher values of dn-AUC6-12h (P < .05). Patients with SLCO1B3 334T/699G alleles had significantly lower dn-AUC6-12h values than homozygotes (P < .05). By introducing body weight, age, and EHC-related factors, including co-administered CNIs and genetic polymorphism of drug transporters, as covariates in the XGboost machine learning model, the prediction performance of AUC0-12h for MPA in Chinese adult renal allograft recipients can be improved.

Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor / 中西医结合学报

OBJECTIVE@#This study was conducted to explore the mechanism of intestinal inflammation and barrier repair in Crohn's disease (CD) regulated by moxibustion through bile acid (BA) enterohepatic circulation and intestinal farnesoid X receptor (FXR).@*METHODS@#Sprague-Dawley rats were randomly divided into control group, CD model group, mild moxibustion group and herb-partitioned moxibustion group. CD model rats induced by 2,4,6-trinitrobenzene sulfonic acid were treated with mild moxibustion or herb-partitioned moxibustion at Tianshu (ST25) and Qihai (CV6). The changes in CD symptoms were rated according to the disease activity index score, the serum and colon tissues of rats were collected, and the pathological changes in colon tissues were observed via histopathology. Western blot, immunohistochemistry (IHC) and immunofluorescence were used to evaluate the improvement of moxibustion on intestinal inflammation and mucosal barrier in CD by the BA-FXR pathway.@*RESULTS@#Mild moxibustion and herb-partitioned moxibustion improved the symptoms of CD, inhibited inflammation and repaired mucosal damage to the colon in CD rats. Meanwhile, moxibustion could improve the abnormal expression of BA in the colon, liver and serum, downregulate the expression of interferon-γ and upregulate the expression of FXR mRNA, and inhibit Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) mRNA. The IHC results showed that moxibustion could upregulate the expression of FXR and mucin2 and inhibit TLR4 expression. Western blot showed that moxibustion inhibited the protein expression of TLR4 and MyD88 and upregulated the expression of FXR. Immunofluorescence image analysis showed that moxibustion increased the colocalization sites and intensity of FXR with TLR4 or nuclear factor-κB p65. In particular, herb-partitioned moxibustion has more advantages in improving BA and upregulating FXR and TLR4 in the colon.@*CONCLUSION@#Mild moxibustion and herb-partitioned moxibustion can improve CD by regulating the enterohepatic circulation stability of BA, activating colonic FXR, regulating the TLR4/MyD88 pathway, inhibiting intestinal inflammation and repairing the intestinal mucosal barrier. Herb-partitioned moxibustion seems to have more advantages in regulating BA enterohepatic circulation and FXR activation. Please cite this article as: Shen JC, Qi Q, Han D, Lu Y, Huang R, Zhu Y, Zhang LS, Qin XD, Zhang F, Wu HG, Liu HR. Moxibustion improves experimental colitis in rats with Crohn's disease by regulating bile acid enterohepatic circulation and intestinal farnesoid X receptor. J Integr Med. 2023; 21(2): 194-204.

Succinate communicates pro-inflammatory signals to the host and regulates bile acid enterohepatic metabolism in a pig model.

Succinate is produced by both the host and microbiota with pleiotropic functions in the modulation of intestinal inflammation and metabolic homeostasis, but the mechanisms remain elusive. This study aimed to determine whether dietary succinate influences the intestinal inflammatory response and to analyze the possible mechanisms by which succinate regulates enterohepatic metabolism. Sixteen growing barrows were randomly assigned to two groups, fed with a basal diet that consisted of a typical commercial diet or fed with a basal diet supplemented with 1% sodium succinate. Our data showed that dietary succinate activated the expression of succinate receptor 1 (SUCNR1) and increased the concentrations of pro-inflammatory cytokines in the intestine. Dietary succinate inhibited the expression levels of the ileal Farnesol X receptor (FXR) and its target genes, promoted hepatic bile acid secretion, and altered the bile acid metabolic profile. Then, we demonstrated that the pro-inflammatory cytokines triggered by succinate disrupted the ability of bile acids to activate FXR and fibroblast growth factor 19. Furthermore, dietary succinate reduced the abundance of bile-salt hydrolase enriched bacteria in the ileum. Taken together, dietary succinate activated the pro-inflammatory response via SUCNR1 in the intestine, and the pro-inflammatory cytokines induced by succinate blocked the activation of FXR and its target genes and disturbed bile acid enterohepatic circulation.

Enhanced Oral Absorption and Liver Distribution of Polymeric Nanoparticles through Traveling the Enterohepatic Circulation Pathways of Bile Acid.

The intestinal epithelium is known to be a main hindrance to oral delivery of nanoparticles. Even though surface ligand modification can enhance cellular uptake of nanoparticles, the "easy entry and hard across" was frequently observed for many active targeting nanoparticles. Here, we fabricated polymeric nanoparticles relayed by bile acid transporters with monomethoxy poly(ethylene glycol)-poly(D,l-lactide) and deoxycholic acid-conjugated poly(2-ethyl-2-oxazoline)-poly(D,l-lactide) based on structural characteristics of intestine epithelium and the absorption characteristics of endogenous substances. As anticipated, deoxycholic acid-modified polymeric nanoparticles featuring good stability in simulated gastrointestinal fluid could notably promote the internalization of their payload by Caco-2 cells through mediation of apical sodium-dependent bile acid transporter (ASBT) and transmembrane transport of the nanoparticles across Caco-2 cell monolayers via relay-guide of ASBT, ileal bile acid-binding protein, and the heteromeric organic solute transporter (OSTα-OSTß) along with multidrug resistance-associated protein 3 (MRP3) evidenced by competitive inhibition and fluorescence immunoassay, which was further visually confirmed by the stronger fluorescence from C6-labeled nanoparticles inside enterocytes and the basal side of the intestinal epithelium of mice. The transcellular transport of deoxycholic acid-modified nanoparticles in an intact form was mediated by caveolin/lipid rafts and clathrin with intracellular trafficking trace of endosome-lysosome-ER-Golgi apparatus and bile acid transport route. Furthermore, the increased uptake by HepG2 cells compared with unmodified nanoparticles evidenced the target ability of deoxycholic acid-modified nanoparticles to the liver, which was further supported by ex vivo imaging of excised major organs of mice. Thus, this study provided a feasible and potential strategy to further enhance transepithelial transport efficiency and liver-targeted ability of nanoparticles by means of the specific enterohepatic circulation pathways of bile acid.

N-(4-[18F]fluorobenzyl)cholylglycine, a potential tracer for positron emission tomography of enterohepatic circulation and drug-induced inhibition of ileal bile acid transport. A proof-of-concept PET/CT study in pigs.

INTRODUCTION: Enterohepatic circulation (EHC) of conjugated bile acids is an important physiological process crucial for bile acids to function as detergents and signal carriers. Perturbation of the EHC by disease or drugs may lead to serious and life-threatening liver and gastrointestinal disorders. In this proof-of-concept study in pigs, we investigate the potential of N-(4-[18F]fluorobenzyl)cholylglycine ([18F]FBCGly) as tracer for quantitative positron emission tomography (PET) of the EHC of conjugated bile acids. METHODS: The biodistribution of [18F]FBCGly was investigated by PET/CT in domestic pigs following intravenous and intraileal administration of the tracer. Hepatic kinetics were estimated from PET and blood data using a 2-tissue compartmental model and dual-input of [18F]FBCGly. The ileal uptake of [18F]FBCGly was investigated with co-injection of nifedipine and endogenous cholyltaurine. Dosimetry was estimated from the PET data using the Olinda 2.0 software. Blood, bile and urine samples were analyzed for possible fluorine-18 labelled metabolites of [18F]FBCGly. RESULTS: [18F]FBCGly was rapidly taken up by the liver and excreted into bile, and underwent EHC without being metabolized. Both nifedipine and endogenous cholyltaurine inhibited the ileal uptake of [18F]FBCGly. The flow-dependent hepatic uptake clearance was estimated to median 1.2 mL blood/min/mL liver tissue. The mean residence time of [18F]FBCGly in hepatocytes was 4.0 ± 1.1 min. Critical organs for [18F]FBCGly were the gallbladder wall (0.94 mGy/MBq) and the small intestine (0.50 mGy/MBq). The effective dose for [18F]FBCGly was 36 µSv/MBq. CONCLUSION: We have shown that [18F]FBCGly undergoes EHC in pigs without being metabolized and that its ileal uptake is inhibited by nifedipine and endogenous bile acids. Combined with our previous findings in rats, we believe that [18F]FBCGly has potential as PET tracer for assessment of EHC of conjugated bile acids under physiological conditions as well as conditions with perturbed hepatic and ileal bile acid transport.

Hepatocellular carcinoma: Novel understandings and therapeutic strategies based on bile acids (Review).

Bile acids (BAs) are the major components of bile and products of cholesterol metabolism. Cholesterol is catalyzed by a variety of enzymes in the liver to form primary BAs, which are excreted into the intestine with bile, and secondary BAs are formed under the modification of the gut microbiota. Most of the BAs return to the liver via the portal vein, completing the process of enterohepatic circulation. BAs have an important role in the development of hepatocellular carcinoma (HCC), which may participate in the progression of HCC by recognizing receptors such as farnesoid X receptor (FXR) and mediating multiple downstream pathways. Certain BAs, such as ursodeoxycholic acid and obeticholic acid, were indicated to be able to delay liver injury and HCC progression. In the present review, the structure and function of BAs were introduced and the metabolism of BAs and the process of enterohepatic circulation were outlined. Furthermore, the mechanisms by which BAs participate in the development of HCC were summarized and possible strategies for targeting BAs and key sites of their metabolic processes to treat HCC were suggested.

Ultra-performance chromatography-electrospray tandem mass spectrometry analysis of bile acid profiles in the enterohepatic circulation following geniposide and acetaminophen-induced liver injury.

Bile acids (BAs) play an important role in pre-diagnosing drug-induced liver injury (DILI). However, in clinical practice, different types of liver injury are characterized by different pathogeneses and pathological manifestations. Therefore, whether BAs can be used as biomarkers across different DILIs remains unclear. In this study, an ultra-performance chromatography-mass spectrometry (MS)/MS-based technique was developed for the simultaneous quantitative analysis of 31 BAs in the serum, liver, feces, urine, and intestinal contents of rats treated with acetaminophen (APAP) and geniposide to induce liver injury. The total extraction recovery for representative analytes ranged between 80.60% and 99.23% in the serum, urine, liver, feces, and intestinal contents. The correlation coefficients for all standard curves of the different matrices were at least 0.99. Validation of the BA analytical method including selectivity, residue, lower limit of quantification, accuracy, precision, matrix effect, and stability conformed with the biospecimen quality control standards of the Chinese Pharmacopoeia (version 2020). Serum biochemical and pathohistological analyses revealed APAP- and geniposide-induced hepatocellular and cholestatic DILI, respectively, with different effects on BA profiles in the enterohepatic circulation. Metabolomics further revealed that the trends in BA changes in the serum, feces, urine, and intestinal tissues were consistent between the geniposide- and APAP-treated groups. However, in the liver, the total BAs (TBA) concentration increased by 1.70 fold in the geniposide group but decreased by 43% in the APAP group compared with the control group. Multivariate analysis revealed differentially expressed BAs, including TCA, CA, and GCA, which are potential biomarkers for DILI, in the serum, liver, and urine following treatment with geniposide. Interestingly, the differentially expressed BAs in the APAP group were similar to those in the control group. Additionally, the magnitude of changes in the TBA in the urine (3.3 fold and 15.5 fold in the APAP and geniposide groups, respectively) was higher than that in the blood (290 fold and 640 fold in the APAP and geniposide groups, respectively). However, given the BA profiles after geniposide- and APAP-induced liver injury, BAs were found to be more suitable as biomarkers for diagnosing cholestatic liver injury. Overall, the BA assay developed in this study is rapid, simple, accurate, validated, sensitive, and suitable for analyzing the levels and distribution of BAs in various parts of the enterohepatic circulation.

Targeting bile acid signaling for the treatment of liver diseases: From bench to bed.

Liver diseases and related complications have become one of the leading causes of morbidity and mortality worldwide, yet effective medicine or approved treatment approach is still limited. Thus, novel therapy is urgently required to prevent or at least slow down the growing burden of liver transplantation or even death caused by malignant liver diseases. As the irreplaceable modulator of hepatic and intestinal signaling cascades, bile acids (BAs) play complex physiological as well as pathological roles in regulating energy and immune homeostasis in various liver diseases, including but not limited to metabolic diseases and cholangiopathies, making them highly attractive therapeutic targets. In the current review, recent progress in the research of enterohepatic circulation of BAs and potential therapeutic targets of BAs signaling, especially the development of currently available treatments, including agonizts of FXR and TGR5, analogs of FGF19, inhibitors of ASBT, and the regulation of gut microbiome through fecal microbiota transplantation were extensively summarized. Their protective effects, molecular mechanisms, and outcomes of clinical trials were highlighted. The structural features of these candidates and perspectives for their future development were further discussed. In conclusion, we believe that pharmacological therapies targeting BAs signaling represent promising and efficient strategies for the treatment of complex and multifactorial liver disorders.

Pharmacometric characterization of entero-hepatic circulation processes of orally administered formulations of amiodarone under complex binding kinetics.

AIMS: The aims of this work are (i) to characterize the absorption properties of orally administered formulations at different dose levels, and (ii) to evaluate the impact of entero-hepatic circulation on the time-course of amiodarone (AM) in rats in order to optimize the development of new oral (OR) formulations. METHODS: Intravenous (IV) formulation consisted on a solution of a commercial injectable of AM chlorhydrate. OR formulations included the IV commercial formulation (Trangorex®) (Solution I), an aqueous supramicellar solution of AM chlorhydrate with Polysorbate at 5% (Solution II) and a suspension from Trangorex® tablets (Tablet). Data from 96 male Wistar rats, including 985 AM observations, were analyzed using NONMEM v7.4. RESULTS: The population pharmacokinetic (PK) model assumes linear absorption processes, showing ka of AM from Solution II (Polysorbate 80, 5%) and Solution I increased by 2.5- and 1.62-fold compared to Tablet formulation. OR bioavailability of AM from Tablet, Solution I and Solution II was 37%, 40%, and 50%, respectively. The structural model of AM disposition was adapted from a previously population PK model and expanded by incorporating entero-hepatic reabsorption (EHR) processes, which estimated a 12.3% biliary excretion of AM and complete re-absorption from lumen. CONCLUSIONS: The current population PK model of AM demonstrated the absorption rate enhancement when AM is formulated with supramicellar concentrations of Polysorbate 80. The study design allowed to characterize the EHR of AM and its contribution in the overall AM disposition.

Bile Acids Transporters of Enterohepatic Circulation for Targeted Drug Delivery.

Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes. The focus is laid on the description of specific or less-specific BA transport proteins and their localization. Initially, the reader is provided with essential information about BAs' properties, their systemic flow, metabolism, and functions. Later, the transport processes are described in detail and schematically illustrated, moving step by step from the liver via bile ducts to the gallbladder, small intestine, and colon; this description is accompanied by descriptions of major proteins known to be involved in BA transport. Spillage of BAs into systemic circulation and urine excretion are also discussed. Finally, the review also points out some of the less-studied areas of the enterohepatic circulation, which can be crucial for the development of BA-related drugs, prodrugs, and drug carrier systems.

Impact of route-dependent phase-II gut metabolism and enterohepatic circulation on the bioavailability and systemic disposition of resveratrol in rats and humans: A comprehensive whole body physiologically-based pharmacokinetic modeling.

Resveratrol, a natural polyphenolic phytoalexin, is a dietary supplement that improves the outcomes of metabolic, cardiovascular, and other age-related diseases due to its diverse pharmacological activities. Although there have been several preclinical and clinical investigations of resveratrol, the contributions of gut phase-II metabolism and enterohepatic circulation to the oral bioavailability and pharmacokinetics of resveratrol remain unclear. Furthermore, a physiologically-based pharmacokinetic (PBPK) model that accurately describes and predicts the systemic exposure profiles of resveratrol in clinical settings has not been developed. Experimental data were acquired from several perspectives, including in vitro protein binding and blood distribution, in vitro tissue S9 metabolism, in situ intestinal perfusion, and in vivo pharmacokinetics and excretion studies. Using these datasets, an in-house whole-body PBPK model incorporating route-dependent phase-II (glucuronidation and sulfation) gut metabolism and enterohepatic circulation processes was constructed and optimized for chemical-specific parameters. The developed PBPK model aligned with the observed systemic exposure profiles of resveratrol in single and multiple dosing regimens with an acceptable accuracy of 0.538-0.999-fold errors. Furthermore, the model simulations elucidated the substantial contribution of gut first-pass metabolism to the oral bioavailability of resveratrol and suggested differential effects of enterohepatic circulation on the systemic exposure of resveratrol between rats and humans. After partial modification and verification, our proposed PBPK model would be valuable to optimize dosage regimens and predict food-drug interactions with resveratrol-based natural products in various clinical scenarios.