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Shaoyao Gancao Decoction (SGD), a traditional Chinese medicine, has been proven to have a good liver protection effect, but the mechanism and pharmacodynamic substances of SGD in the treatment of acute liver injury are still unclear. In this study, an ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF-MS) method was established to characterize 107 chemical components of SGD and 12 compounds absorbed in rat plasma samples after oral administration of SGD. Network pharmacology was applied to construct a component-target-pathway network to screen the possible effective components of SGD in acute liver injury. Using lipidomics based on UHPLC-Q-TOF-MS coupled with a variety of statistical analyses, 20 lipid biomarkers were screened and identified, suggesting that the improvement of acute liver injury by SGD was involved in cholesterol metabolism, glycerol-phospholipid metabolism, sphingolipid signaling pathways and fatty acid biosynthesis. In addition, the UHPLC-tandem MS method was established for pharmacokinetics analysis, and 10 potential active components were determined simultaneously within 12 min through the optimization of 0.1% formic acid water and acetonitrile as a mobile phase system. A Pharmacokinetics study showed that paeoniflorin, albiflorin, oxypaeoniflorin, liquiritigenin, isoliquiritigenin, liquiritin, ononin, formononetin, glycyrrhizic acid, and glycyrrhetinic acid as the potential active compounds of SGD curing acute liver injury., (© 2024 Wiley‐VCH GmbH.)

Getting the dose right is a key challenge in drug development; model-informed drug development (MIDD) provides powerful tools to shape dose strategies and inform decision making. In this tutorial, the case study of the ZENITH trials showcases how a set of clinical pharmacology and MIDD approaches informed an impactful dose strategy. The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, has yielded a robust and significant albuminuria reduction in the Phase IIb trial ZENITH-CKD and is being investigated for reduction of kidney function decline in a high-risk chronic kidney disease population in the Phase III trial ZENITH High Proteinuria. Endothelin antagonist treatment has, until now, been limited by the class effect fluid retention. ZENITH-CKD investigated a wide range of zibotentan doses based on pharmacokinetics in renal impairment, competitor-data exposure-response modeling, and clinical trial simulations. Recruitment delays reduced interim analysis data availability; here, supportive dose-response modeling recovered decision-making confidence. At trial completion, the low-dose arm enabled Phase III dose selection between Phase IIb doses. Dose-response modeling of efficacy and Kaplan-Meier analyses of tolerability identified a kidney-function-based low-dose strategy of 0.25 or 0.75 mg zibotentan (with 10 mg dapagliflozin) to balance benefit/risk in ZENITH High Proteinuria. The applied clinical pharmacology and MIDD principles enabled successful Phase IIb dose finding, rationalized and built confidence in the innovative Phase III dosing strategy and identified a potential therapeutic window for zibotentan/dapagliflozin, providing the opportunity for a significant improvement in the treatment of chronic kidney disease with high proteinuria., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The co-administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P-glycoprotein, there is a plausible potential for drug-drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co-administered, we have established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug-drug interactions were examined by the LC-MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco-2 cells. The results showed that DPF significantly increased the area under the curve (AUC (0-t) ) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h μg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC (0-t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h μg/L) of valsartan after oral co-administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1- and 1.25-fold at 2.25 h. Caco-2 cell uptake studies confirmed that P-glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug-drug interactions in the treatment of heart failure and provides a guidence for clinical therapy., (© 2024 John Wiley & Sons, Ltd.)

Aims: The aim of this work is to compare empagliflozin systemic exposure between patients with heart failure (HF) and patients with type 2 diabetes (T2D)., Methods: Analysis of covariance (ANCOVA) compared steady state trough concentrations of empagliflozin 10 mg in EMPEROR-reduced (patients with HF with reduced ejection fraction [HFrEF]) and EMPA-REG OUTCOME (patients with T2D at high cardiovascular risk) after adjusting for eGFR and body weight., Results: The difference in geometric Mean (gMean) empagliflozin steady state trough concentration of 10 mg empagliflozin between EMPEROR-reduced and EMPA-REG OUTCOME was 1.47-fold (95% confidence interval [CI]: 1.33, 1.63). Additionally, ANCOVA for the sub-group of patients with both T2D and HF conditions revealed a difference in gMean steady state trough concentration of 1.53-fold (95% CI: 1.26, 1.85). In both patients with HFrEF and HF with preserved EF (HFpEF), there was no major difference in empagliflozin steady state trough exposure by New York Heart Association (NYHA) classification or by use of angiotensin receptor-neprilysin inhibitor as comedication. A weak positive correlation was observed for NT-proBNP at Week 12 and empagliflozin steady state trough concentration in both patients with HFrEF and HFpEF (Pearson correlation r = 0.19)., Conclusions: Plasma concentrations of empagliflozin in patients with HF were higher compared to patients with T2D, but the exposure resulting from the 10 mg dose was still below the exposure resulting from the dose of 25 mg approved in patients with T2D. The difference in exposure was attributable to demographic characteristics and HF-induced pathophysiological changes. Overall, the results confirm 10 mg as the appropriate empagliflozin dose in patients with HF., (© 2024 Boehringer Ingelheim Pharma GmbH & Co. KG. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Chronic kidney disease (CKD) is a complication of diabetes that affects circulating drug concentrations and elimination of drugs from the body. Multiple drugs may be prescribed for treatment of diabetes and co-morbidities, and CKD complicates the pharmacotherapy selection and dosing regimen. Characterizing variations in renal drug clearance using models requires large clinical datasets that are costly and time-consuming to collect. We propose a flexible approach to incorporate impaired renal clearance in pharmacokinetic (PK) models using descriptive statistics and secondary data with mechanistic models and PK first principles. Probability density functions were generated for various drug clearance mechanisms based on the degree of renal impairment and used to estimate the total clearance starting from glomerular filtration for metformin (MET) and dapagliflozin (DAPA). These estimates were integrated with PK models of MET and DAPA for simulations. MET renal clearance decreased proportionally with a reduction in estimated glomerular filtration rate (eGFR) and estimated net tubular transport rates. DAPA total clearance varied little with renal impairment and decreased proportionally to reported non-renal clearance rates. Net tubular transport rates were negative to partially account for low renal clearance compared with eGFR. The estimated clearance values and trends were consistent with MET and DAPA PK characteristics in the literature. Dose adjustment based on reduced clearance levels estimated correspondingly lower doses for MET and DAPA while maintaining desired dose exposure. Estimation of drug clearance rates using descriptive statistics and secondary data with mechanistic models and PK first principles improves modeling of CKD in diabetes and can guide treatment selection., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Proline henagliflozin, a novel selective inhibitor of sodium glucose cotransporter 2, is a treatment for type 2 diabetes mellitus. We designed a parallel-group, open-label, and multicenter study to evaluate the pharmacokinetic (PK), pharmacodynamic (PD), and safety profiles of henagliflozin in Chinese subjects with varying degrees of liver dysfunction. Thirty-two subjects were enrolled and divided into four groups based on liver function (normal liver function, mild, moderate, or severe liver dysfunction). The area under the plasma concentration from time zero to infinity of henagliflozin in subjects with mild liver dysfunction, moderate liver dysfunction, and severe liver dysfunction compared with normal liver function was increased by 137%, 197%, and 204%, respectively. The maximum plasma concentration was also increased by 123%, 129%, and 139%, respectively. PK parameters of three metabolites varied to different degrees in the liver dysfunction groups than in the normal liver function group. The mean accumulative excretion amounts and fraction of dose excreted in urine expressed as a percentage were all increased with the decrease of liver function. The PD parameters were significantly higher in liver dysfunction groups than those in the normal liver function group. However, the urine creatinine (U Cr ) was not significantly different among the groups. No notable adverse events or adverse drug reactions were observed. Due to the higher exposures in subjects with liver dysfunction, the benefit: risk ratio should be individually assessed because the long-term safety profile and efficacy have not been specifically studied in this population., (© 2024, The American College of Clinical Pharmacology.)

Liquiritin (LQ), a kind of flavonoid isolated from licorice, was proven to have great potential in treating heart failure. Pharmacokinetic evaluation is important for demonstrating clinical efficacy and mechanisms, and the prototype drug and its metabolite profiling are important for drug discovery and development. However, the metabolism of LQ in acute myocardial infarction (AMI) model rats still needs to be studied in depth. An information-dependent acquisition (IDA)-ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method was applied to profile LQ metabolites in AMI model rat plasma. Protein precipitation and extraction were used for sample preparation. Chromatographic separation was achieved using an XSelect BEH C 18 column (2.1 × 150 mm, 2.5 μm) using gradient elution method combining 0.1% formic acid and acetonitrile with a flow rate of 0.3 mL/min. Twelve metabolites were identified in IDA mode, sulfation, glucuronidation, methylation, methyl esterification, glutamine conjugation, and valine conjugation, and their composite reactions were presumed as the primary pathways of LQ metabolism. The variation in the peak areas showed that the time to reach the peak drug concentration of LQ and 12 metabolites was within 5 h. In summary, IDA-bridged UHPLC-MS/MS from characteristic fragment ions toward confidence-enhanced identification could effectively screen and profile metabolites., (© 2024 John Wiley & Sons Ltd.)

Geraniin (GE), an ellagitannin (ET) renowned for its promising health advantages, faces challenges in its practical applications due to its limited bioavailability. This innovative and novel formulation of GE and soy-phosphatidylcholine (GE-PL) complex has the potential to increase oral bioavailability, exhibiting high entrapment efficiency of 100.2 ± 0.8 %, and complexation efficiency of 94.6 ± 1.1 %. The small particle size (1.04 ± 0.11 μm), low polydispersity index (0.26 ± 0.02), and adequate zeta potential (-26.1 ± 0.12 mV), indicate its uniformity and stability. Moreover, the formulation also demonstrates improved lipophilicity, reduced aqueous and buffer solubilities, and better partition coefficient. It has been validated by various analytical techniques, including Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) studies. Oral bioavailability and pharmacokinetics of free GE and GE-PL complex investigated in rabbits demonstrated enhanced plasma concentration of ellagic acid (EA) compared to free GE. Significantly, GE, whether in its free form or as part of the GE-PL complex, was not found in the circulatory system. However, EA levels were observed at 0.5 h after administration, displaying two distinct peaks at 2 ± 0.03 h (T1 max ) and 24 ± 0.06 h (T2 max ). These peaks corresponded to peak plasma concentrations (C1 max and C2 max ) of 588.82 ng/mL and 711.13 ng/mL respectively, signifying substantial 11-fold and 5-fold enhancements when compared to free GE. Additionally, it showed an increased area under the curve (AUC), the elimination half-life (t 1/2 , el) and the elimination rate constant (K el ). The formulation of the GE-PL complex prolonged the presence of EA in the bloodstream and improved its absorption, ultimately leading to a higher oral bioavailability. In summary, the study highlights the significance of the GE-PL complex in overcoming the bioavailability limitations of GE, paving the way for enhanced therapeutic outcomes and potential applications in drug delivery and healthcare., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Usha Sundralingam reports financial support was provided by Malaysia Ministry of Higher Education. Uma Devi Palanisamy has patent appoved to Uma Devi Palanisamy (Patent application number: PI2017704622). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.]., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: To explore the effect of renal function on the pharmacokinetic (PK) and pharmacodynamic (PD) profile and safety of enavogliflozin, a selective sodium-glucose cotransporter 2 (SGLT2) inhibitor, in patients with type 2 diabetes mellitus (T2DM)., Methods: An open-label, two-part clinical trial was conducted in T2DM patients, stratified by renal function: Group 1, normal renal function; Group 2, mild renal impairment (RI); Group 3, moderate RI; and Group 4, severe RI. In Part A, Groups 2 and 4 received enavogliflozin 0.5 mg once. In Part B, Groups 1 and 3 received enavogliflozin 0.5 mg once daily for 7 days. Serial blood and timed urine samples were collected to analyse the PK and PD characteristics of enavogliflozin. Pearson's correlation coefficients were calculated to assess the correlations between PK or PD parameters and creatinine clearance (CrCL)., Results: A total of 21 patients completed the study as planned. The area under the curve (AUC) for enavogliflozin was not significantly correlated with CrCL, although the maximum concentration slightly decreased as renal function decreased. By contrast, daily urinary glucose excretion (UGE) was positively correlated with CrCL after both single- (r = 0.7866, p < 0.0001) and multiple-dose administration (r = 0.6606, p = 0.0438)., Conclusions: Systemic exposure to oral enavogliflozin 0.5 mg was similar among the patients with T2DM regardless of their renal function levels. However, the glucosuric effect of enavogliflozin decreased with RI. Considering the UGE observed and approved therapeutic use of other SGLT2 inhibitors, the efficacy of enavogliflozin with regard to glycaemic control could be explored in patients with mild and moderate RI (estimated glomerular filtration rate ≥30 or ≥45 mL/min/1.73 m 2 ) in a subsequent larger study., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

SHPL-49 is an innovative glycoside derivative that is synthesized by structural modifications of salidroside，demonstrating therapeutic effects on animal models of ischemia in pre-clinical experiments. A phase I, single-center, randomized, double-blind, placebo-controlled, single and multiple dose administration study of SHPL-49 was conducted in healthy Chinese volunteers. In single-ascending-dose (SAD) study, 32 subjects randomized 6:2 to receive SHPL-49 (30 mg, 75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion. In multiple-ascending-dose (MAD) study, subjects were randomized 6:2 to receive SHPL-49 (75 mg, 150 mg, 300 mg) or placebo with 30 minutes infusion every 8 h for 7 days. Safety evaluations were conducted throughout the studies. Plasma and urine concentrations of SHPL-49 were detected and its metabolites were identified. Pharmacokinetic parameters were calculated using noncompartmental methods. SHPL-49 was generally safe and well-tolerated at single ascending doses (30-300 mg) and multiple ascending doses (75-300 mg). All adverse events were mild and resolved without any intervention. No serious adverse events were reported. In the SAD study, SHPL-49 exhibited dose-proportional plasma pharmacokinetics, with peak plasma concentration (C max ) ranging from 673.83 to 6275.00 ng/mL, area under the plasma concentration-time curve (AUC 0-t ) ranging from 338.57 to 3732.67 h·ng/mL, and elimination half-life (t 1/2 ) ranging from 0.49 to 0.67 h. In the MAD, the exposure was also dose-proportional and there was no significant accumulation following multiple dosing. Four metabolites were identified in urine and plasma. SHPL-49 shows a favorable pharmacokinetic, safety, and tolerability profile in healthy Chinese volunteers following a single- and multiple-ascending- dose administration in this study. For future therapeutic investigations, it is recommended to administer SHPL-49 intravenously at 8-hour intervals with a dosage range of 150-300 mg., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

The aim of this study was to use a combination of physiologically based pharmacokinetic (PBPK) modeling and urinary glucose excretion (UGE) modeling to predict the time profiles of pharmacokinetics (PK) and UGE for the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMP). Additionally, the study aims to explore the compensatory effect of SGLT1 in renal glucose reabsorption (RGR) when SGLT2 is inhibited. The PBPK-UGE model was developed using physicochemical and biochemical properties, renal physiological parameters, binding kinetics, glucose, and Na + reabsorption kinetics by SGLT1/2. For area under the plasma concentration-time curve, maximum plasma concentration, and cumulative EMP excretion in urine, the predicted values fell within a range of 0.5-2.0 when compared to observed data. Additionally, the simulated UGE data also matched well with the clinical data, further validating the accuracy of the model. According to the simulations, SGLT1 and SGLT2 contributed approximately 13% and 87%, respectively, to RGR in the absence of EMP. However, in the presence of EMP at doses of 2.5 and 10 mg, the contribution of SGLT1 to RGR significantly increased to approximately 76%-82% and 89%-93%, respectively, in patients with type 2 diabetes mellitus. Furthermore, the model supported the understanding that the compensatory effect of SGLT1 is the underlying mechanism behind the moderate inhibition observed in total RGR. The PBPK-UGE model has the capability to accurately predict the PK and UGE time profiles in humans. Furthermore, it provides a comprehensive analysis of the specific contributions of SGLT1 and SGLT2 to RGR in the presence or absence of EMP., (© 2024, The American College of Clinical Pharmacology.)

Background: Some glucoside drugs can be transported via intestinal glucose transporters (IGTs), and the presence of carbohydrate excipients in pharmaceutical formulations may influence the absorption of them. This study, using gastrodin as probe drug, aimed to explore the effects of fructose, lactose, and arabic gum on intestinal drug absorption mediated by the glucose transport pathway., Methods: The influence of fructose, lactose, and arabic gum on gastrodin absorption was assessed via pharmacokinetic experiments and single-pass intestinal perfusion. The expression of sodium-dependent glucose transporter 1 (SGLT1) and sodium-independent glucose transporter 2 (GLUT2) was quantified via RT‒qPCR and western blotting. Alterations in rat intestinal permeability were evaluated through H&E staining, RT‒qPCR, and immunohistochemistry., Results: Fructose reduced the area under the curve (AUC) and peak concentration (C max ) of gastrodin by 42.7% and 63.71%, respectively (P < 0.05), and decreased the effective permeability coefficient (P eff ) in the duodenum and jejunum by 58.1% and 49.2%, respectively (P < 0.05). SGLT1 and GLUT2 expression and intestinal permeability remained unchanged. Lactose enhanced the AUC and C max of gastrodin by 31.5% and 65.8%, respectively (P < 0.05), and increased the P eff in the duodenum and jejunum by 33.7% and 26.1%, respectively (P < 0.05). SGLT1 and GLUT2 levels did not significantly differ, intestinal permeability increased. Arabic gum had no notable effect on pharmacokinetic parameters, SGLT1 or GLUT2 expression, or intestinal permeability., Conclusion: Fructose, lactose, and arabic gum differentially affect intestinal drug absorption through the glucose transport pathway. Fructose competitively inhibited drug absorption, while lactose may enhance absorption by increasing intestinal permeability. Arabic gum had no significant influence., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Henagliflozin is an original, selective sodium-glucose cotransporter 2 (SGLT2) inhibitor. Hydrochlorothiazide (HCTZ) is a common anti-hypertensive drug. This study aimed to evaluate the potential interaction between henagliflozin and HCTZ., Methods: This was a single-arm, open-label, multi-dose, three-period study that was conducted in healthy Chinese volunteers. Twelve subjects were treated in three periods, period 1: 25 mg HCTZ for four days, period 2: 10 mg henagliflozin for four days and period 3: 25 mg HCTZ + 10 mg henagliflozin for four days. Blood samples and urine samples were collected before and up to 24 hours after drug administrations on day 4, day 10 and day 14. The plasma concentrations of henagliflozin and HCTZ were analyzed using LC-MS/MS. The urine samples were collected for pharmacodynamic glucose and electrolyte analyses. Tolerability was also evaluated., Results: The 90% CI of the ratio of geometric means (combination: monotherapy) for AUC τ,ss of henagliflozin and HCTZ was within the bioequivalence interval of 0.80-1.25. For henagliflozin, co-administration increased C ss, max by 24.32% and the 90% CI of the GMR was (108.34%, 142.65%), and the 24-hour urine volume and glucose excretion decreased by 0.43% and 19.6%, respectively. For HCTZ, co-administration decreased C ss, max by 19.41% and the 90% CI of the GMR was (71.60%, 90.72%), and the 24-hour urine volume and urinary calcium, potassium, phosphorus, chloride, and sodium excretion decreased by 11.7%, 20.8%, 11.8%, 11.9%, 22.0% and 15.5%, respectively. All subjects (12/12) reported adverse events (AEs), but the majority of theses AEs were mild and no serious AEs were reported., Conclusion: Although C ss,max was affected by the combination of henagliflozin and HCTZ, there was no clinically meaningful safety interaction between them. Given these results, coadministration of HCTZ should not require any adaptation of henagliflozin dosing., Trial Registration: ClinicalTrials.gov NCT06083116., Competing Interests: Sheng Feng is a devoted full-time employee of Jiangsu Hengrui Pharmaceuticals Co., Ltd. We would like to state that we have no other conflicts of interest pertaining to the content of this article., (© 2024 Chen et al.)

Saposhnikoviae Radix (SR) may enhance the pharmacodynamics of Huangqi Chifeng Tang (HQCFT) in the treatment of cerebral infarction according to our previous research, but the underlying mechanism is unknown. Herein, an in vivo pharmacokinetic assay in rats and in vitro MDCK-MDR1 cell assays were used to investigate the possible mechanism of SR, its main components, and its interactions with Astragali Radix (AR) and Paeoniae Radix (PR). An ultrahigh-performance liquid chromatography-tandem mass spectrometry (UPLC‒MS/MS)-based analytical method for quantifying astragaloside IV (ASIV) and paeoniflorin (PAE) in microdialysis and transport samples was developed. The pharmacokinetic parameters of SR were determined using noncompartmental analyses CCK-8 assays were used to detect the cytotoxicity of ASIV, PAE, cimifugin (CIM), prim-o-glucosylcimifugin (POG) and their combinations. Moreover, drug transport was studied using MDCK-MDR1 cells. Western blotting was performed to measure the protein expression levels of P-GP and MRP1. Claudin-5, ZO-1, and F-actin expression was determined via immunohistochemical staining of MDCK-MDR1 cells. harmacokinetic studies revealed that, compared with those of Huangqi Chifeng Tang-Saposhnikoviae Radix (HQCFT-SR), the T max of ASIV increased by 11.11 %, and the MRT 0-t and T max of PAE increased by 11.19 % and 20 %, respectively, in the HQCFT group. Transport studies revealed that when ASIV was coincubated with 28 μM CIM or POG, the apparent permeability coefficient (P app ) increased by 71.52 % and 50.33 %, respectively. Coincubation of PAE with 120 μM CIM or POG increased the P app by 87.62 % and 60.95 %, respectively. Moreover, CIM and POG significantly downregulated P-gp and MRP1 (P < 0.05), inhibited the expression of Claudin-5, ZO-1, and F-actin (P < 0.05), and affected intercellular tight junctions (TJs). In conclusion, our study successfully established a selective, sensitive and reproducible UPLC‒MS/MS analytical method to detect drug‒drug interactions between SR, AR and PR in vivo and in vitro, which is beneficial for enhancing the therapeutic efficacies of AR and PR. Moreover, this study provides a theoretical basis for further research on the use of SR as a drug carrier., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Introduction: In adults, sodium-glucose cotransporter type 2 inhibitors have revolutionised the treatment of type 2 diabetes mellitus, heart failure, and chronic kidney disease., Objective: We aimed to review information on compassionate use, clinical pharmacology, efficacy, and safety of dapagliflozin and empagliflozin in children., Methods: We conducted a systematic review of published clinical trials, case reports, and observational studies in Medline, Excerpta Medica, and Web of Science databases from inception to September 2023. For the two randomised controlled trials on type 2 diabetes mellitus (T2DM), we implemented a meta-analysis on the primary outcome (mean difference in glycosylated haemoglobin [HbA1c] between intervention and placebo groups). Review Manager (RevMan), version 5.4.1, was used for this purpose., Results: Thirty-five articles (nine case reports, ten case series, one prospective non-controlled trial, four controlled randomised trials, two surveys, six pharmacokinetic studies, and three pharmacovigilance studies) were selected, in which 415 children were exposed to either dapagliflozin or empagliflozin: 189 diabetic patients (mean age 14.7 ± 2.9 years), 32 children with glycogen storage disease type Ib (GSD Ib), glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency, or severe congenital neutropenia type 4 (8.5 ± 5.1 years), 47 children with kidney disease or heart failure (11.2 ± 6.1 years), 84 patients in pharmacokinetic studies (15.1 ± 2.3 years), and 63 patients in toxicological series. The effect of dapagliflozin and empagliflozin in T2DM was demonstrated by HbA1c reduction in two randomised trials among a total of 177 adolescents, with a mean HbA1c difference of -0.82% (95% confidence interval -1.34 to -0.29) as compared to placebo (no heterogeneity, I 2 = 0%). Dosage ranged between 5 and 20 mg (mean 11.4 ± 3.7) once daily for dapagliflozin and between 5 and 25 mg (mean 15.4 ± 7.4) once daily for empagliflozin. Among the paediatric cases of GSD Ib, empagliflozin 0.1-1.3 mg/kg/day improved neutropenia, infections, and gastrointestinal health. Dapagliflozin (mean dosage 6.9 ± 5.2 mg once daily) was well-tolerated in children with chronic kidney disease and heart failure. Side effects were generally mild, the most frequent being hypoglycaemia in children with GSD Ib (33% of patients) or T2DM (14% of patients) on concomitant hypoglycaemic drugs. Diabetic ketoacidosis is rare in children., Conclusion: Early evidence suggests that dapagliflozin and empagliflozin are well tolerated in children. A clinical pharmacology rationale currently exists only for adolescents with diabetes mellitus., Prospero Registration Number: CRD42023438162., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Empagliflozin is a sodium glucose co-transporter-2 (SGLT2) inhibitor that has gained significant attention in the treatment of type 2 diabetes mellitus. Understanding its chemistry, pharmacology, and toxicology is crucial for the safe and effective use of this medication., Objective: This review aims to provide a comprehensive overview of the chemistry, pharmacology, and toxicology of empagliflozin, synthesizing the available literature to present a concise summary of its properties and implications for clinical practice., Methods: A systematic search of relevant databases was conducted to identify studies and articles related to the chemistry, pharmacology, and toxicology of empagliflozin. Data from preclinical and clinical studies, as well as post-marketing surveillance reports, were reviewed to provide a comprehensive understanding of the topic., Results: Empagliflozin is a selective SGLT2 inhibitor that works by constraining glucose reabsorption in the kidneys, causing increased urinary glucose elimination. Its unique mechanism of action provides glycemic control, weight reduction, and blood pressure reduction. The drug's chemistry is characterized by its chemical structure, solubility, and stability. Pharmacologically, empagliflozin exhibits favorable pharmacokinetic properties with rapid absorption, extensive protein binding, and renal elimination. Clinical studies have demonstrated its efficacy in improving glycemic control, reducing cardiovascular risks, and preserving renal function. However, adverse effects, for instance, urinary tract infections, genital infections, and diabetic ketoacidosis have been reported. Toxicological studies indicate low potential for organ toxicity, mutagenicity, or carcinogenicity., Conclusion: Empagliflozin is a promising SGLT2 inhibitor that offers an innovative approach to the treatment of type 2 diabetes mellitus. Its unique action mechanism and favorable pharmacokinetic profile contribute to its efficacy in improving glycemic control and reducing cardiovascular risks. While the drug's safety profile is generally favorable, clinicians should be aware of potential adverse effects and monitor patients closely. More study is required to determine the longterm safety and explore potential benefits in other patient populations. Overall, empagliflozin represents a valuable addition to the armamentarium of antidiabetic medications, offering significant benefits to patients suffering from type 2 diabetes mellitus. This study covers all aspects of empagliflozin, including its history, chemistry, pharmacology, and various clinical studies, case reports, and case series., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Total glucosides picrorhizae rhizome (TGPR) is an innovative traditional Chinese medicine, which is a candidate drug for the treatment of nonalcoholic steatohepatitis (NASH). However, there is still lack of deep research on the behaviors of TGPR in vivo. In this study, a reliable, specific, and sensitive liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method has been constructed for simultaneous determination of picroside I, picroside II, vanillic acid, androsin, cinnamic acid and picroside IV, the major active constituents of TGPR, in rat various biological matrices (plasma, tissue, bile, urine and feces) using diphenhydramine hydrochloride and paeoniflorin as the internal standard. All biosamples were prepared using a simple protein precipitation with acetonitrile. Chromatographic separation was achieved on a waters UHPLC® HSS T3 (100×2.1 mm, 1.8 μm) column. The mobile phase consisted of methanol: acetonitrile1(1:1, V/V) and 0.5 mM ammonium formate in water, was employed to separate six components from endogenous interferences. The components were detected with a triple quadrupole mass spectrometer using positive and negative ion multiple reaction monitoring (MRM) mode. The newly developed method was successfully applied to investigate the pharmacokinetics, tissue distribution and excretion of six components in rats. The pharmacokinetic results indicated that the six components in TGPR could be quickly absorbed and slowly eliminated and their bioavailability were less than 12.37%, which implied the poor absorption after intragastric dosing. For tissue distribution, the six components in TGPR were detected in liver and only androsin could penetrate the blood-brain barrier. Meanwhile, the excretion study demonstrated that vanillic acid was mostly excreted as prototype drugs and the remaining five components might be widely metabolized in vivo as the metabolites, the unconverted form was excreted mainly by feces route. The pharmacokinetics, tissue distribution and excretion characteristics of six bioactive components in TGPR were firstly revealed, which will provide references for further clinical application of TGPR as an anti-NASH drug., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Polygonum multiflorum (PM) has been used as a tonic and anti-aging remedy for centuries in Asian countries. However, its application in the clinic has been hindered by its potential to cause liver injury and the lack of investigations into this mechanism. Here, we established a strategy using a network pharmacological technique combined with integrated pharmacokinetics to provide an applicable approach for addressing this issue. A fast and sensitive HPLC-QQQ-MS method was developed for the simultaneous quantification of five effective compounds (trans-2,3,5,4'-tetrahydroxystilbene-2- O -β-d-glucoside, emodin-8- O -β-d-glucoside, physcion-8- O -β-d-glucoside, aloe-emodin and emodin). The method was fully validated in terms of specificity, linearity, accuracy, precision, extraction recovery, matrix effects, and stability. The lower limits of quantification were 0.125-0.500 ng/mL. This well-validated method was successfully applied to an integrated pharmacokinetic study of PM extract in rats. The network pharmacological technique was used to evaluate the potential liver injury due to the five absorbed components. Through pathway enrichment analysis, it was found that potential liver injury is primarily associated with PI3K-Akt, MAPK, Rap1, and Ras signaling pathways. In brief, the combined strategy might be valuable in revealing the mechanism of potential liver injury due to PM.

Background: Astragali Radix-Safflower combination (ARSC) is widely utilized in clinic to treat cerebral ischemia/reperfusion injury (CI/RI). Whereas, there is no in-depth research of the pharmacokinetics (PK) and pharmacodynamics (PD) analysis of ARSC after intragastric administration in rats with CI/RI., Purpose: The purpose of this research is to investigate the PK characteristics of eight active ingredients (astragaloside IV, calycosin, calycosin-7-O-β-glucoside, formononetin, ononin, hydroxysafflor yellow A, syringin and vernine) of ARSC, and the regulation of neurotransmitters disorders, revealing the pharmacodynamic substance basis and the mechanism of ARSC in treating CI/RI from the molecular level., Methods: We established a new method which based on blood-brain dual channel microdialysis (MD) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) to continuously gather, and determine the components of ARSC and neurotransmitters related to CI/RI in vivo. The collected data were analyzed by sigmoid-E max function. The neurotransmitters primarily regulated in CI/RI rat were discussed by principal component analysis and the compound most associated with total pharmacodynamics was chosen by partial least squares regression., Results: The validated LC-MS/MS method had specificity and selectivity to simultaneously analyze the concentration of eight active components of ARSC extract and five neurotransmitters of CI/RI rats. The recovery rates of brain MD probe and blood MD probe were stable within six hours. The MD probes recovery rates decreased with the increase of flow rates, but the solution concentration had little effect on the probes recovery rates. It was feasible to correct the recovery rates of probes in vivo by using reverse dialysis method. All eight active ingredients of ARSC could pass across the blood brain barrier after CI/RI. ARSC regulated the release of glutamate (Glu), γ-aminobutyric acid (GABA), dopamine (DA), 5-hydroxytryptamine (5-HT) and aspartic acid (Asp). Notably, astragaloside IV and hydroxysafflor yellow A might have better regulatory effect on neurotransmitters in comparison with other six measured components of ARSC, and Glu was the neurotransmitter mainly regulated in CI/RI rats., Conclusion: The ARSC was able to treat CI/RI through ameliorating neurotransmitters disorders. There was a hysteresis between the peaked drug concentration and maximum therapeutic effect of ARSC. The drug effective concentrations range of ASIV, calycosin, calycosin-7-O-β-glucoside, syringin and vernine in blood microdialysate and calycosin, syringin, vernine in brain microdialysate were narrow, which need be paid attention in clinical use., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2022. Published by Elsevier GmbH.)

Puerarin (PUR) and gastrodin (GAS) are often used in combined way for treating diseases caused by microcirculation disorders. The current study aimed to investigate the absorption and transportation mechanism of PUR and GAS and their interaction via Caco-2 monolayer cell model. In this work, the concentration in Caco-2 cell of PUR and GAS was determined by HPLC method. The bidirectional transport of PUR and GAS and the inhibition of drug efflux including verapamil and cyclosporine on the transport of these two components were studied. The mutual influence between PUR and GAS, especially the effect of the latter on the former of the bidirectional transport were also investigated. The transport of 50 μg·mL -1 PUR in Caco-2 cells has no obvious directionality. While the transport of 100 and 200 μg·mL -1 PUR presents a strong directionality, and this directionality can be inhibited by verapamil and cyclosporine. When PUR and GAS were used in combination, GAS could increase the absorption of PUR while PUR had no obvious influence on GAS. Therefore, the compatibility of PUR and GAS is reasonable, and GAS can promote the transmembrane transport of PUR, the effect of which is similar to that of verapamil.

The COVID-19 new variants spread rapidly all over the world, and until now scientists strive to find virus-specific antivirals for its treatment. The main protease of SARS-CoV-2 (M pro ) exhibits high structural and sequence homology to main protease of SARS-CoV (93.23% sequence identity), and their sequence alignment indicated 12 mutated/variant residues. The sequence alignment of SARS-CoV-2 main protease led to identification of only one mutated/variant residue with no significant role in its enzymatic process. Therefore, M pro was considered as a high-profile drug target in anti-SARS-CoV-2 drug discovery. Apigenin analogues to COVID-19 main protease binding were evaluated. The detailed interactions between the analogues of Apigenin and SARS-CoV-2 M pro inhibitors were determined as hydrogen bonds, electronic bonds and hydrophobic interactions. The binding energies obtained from the molecular docking of M pro with Boceprevir, Apigenin, Apigenin 7-glucoside-4'-p-coumarate, Apigenin 7-glucoside-4'-trans-caffeate and Apigenin 7-O-beta-d-glucoside (Cosmosiin) were found to be -6.6, -7.2, -8.8, -8.7 and -8.0 kcal/mol, respectively. Pharmacokinetic parameters and toxicological characteristics obtained by computational techniques and Virtual ADME studies of the Apigenin analogues confirmed that the Apigenin 7-glucoside-4'-p-coumarate is the best candidate for SARS-CoV-2 M pro inhibition.

Ethnopharmacological Relevance: Luohanguo (LHG) extract major contenting mogrosides, as a nonnutritive sweetener, has been reported to exert a hypoglycemic effect on diabetic patients and animals. As the pharmacokinetics and pharmacodynamics of drugs were changed with diabetes, it may lead to the different pharmacological of mogrosides between diabetic and normal subjects., Aims of the Study: To characterise the pharmacokinetic profiles of mogrosides in T2DM rats., Study Design and Methods: High-fat diet and streptozocin induced type 2 diabetic mellitus rats were used to investigate the pharmacokinetic behavior of mogroside V and mogrosides IIIA 1 , IIA 1 , and IA 1 after T2DM rats orally administrated with mogroside V and 1-3 glucose residues' mogrosides, respectively. The validated convenient UPLC-QTOF/MS and UPLC-MS/MS methods were established to use in the pharmacokinetic studies of mogrosides in normal and T2DM rats. Additionally, the expression of the intestinal tight junction protein zonula occludens-1 (ZO-1) was also detected by immunohistochemical analysis, which assessed the function of passive intestinal permeability in T2DM rats., Results: The results showed that for rats treated with mogroside V, its metabolite mogroside IIIA 1 has a significant increase (p < 0.05) in maximum plasma concentration (C max , 163.80 ± 25.56 ng/mL) and area under the plasma concentration (AUC 0-t , 2327.44 ± 474.63 h·ng/mL) in T2DM rats compared with in normal rats. The mean residence time (MRT 0-t , 12.04 ± 0.97 h) of mogroside V showed a significant decrease (p < 0.05) in T2DM rats. However, the mogrosides IIIA 1 , IIA 1 and IA 1 showed no statistical differences in the normal and T2DM rats after administered with 1-3 glucose residues' mogrosides. Furthermore, the expression level of ZO-1 in the duodenum and colon of T2DM rats were downregulated., Conclusion: The pharmacokinetic profiles of mogroside V and its metabolite mogroside IIIA 1 in T2DM rats and normal rats showed some difference, it might be affected by the metabolic changes in the pathological state of T2DM., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Hui Medicine ZhaLi NuSi Prescription (ZLNS) is described in "Hui Hui Prescription," and it has been used to treat cerebral infarction in Hui Region, China. In this study, a rapid and reliable ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS) method was established and applied to simultaneously determine geniposidic acid, oxypaeoniflorin, hydroxysafflor yellow A, caffeic acid, magnoflorine, paeoniflorin, ferulic acid, β-ecdysterone, icariin, rhein, and baohuoside I in rat plasma. The pharmacokinetic parameters of these components and the influence of essential oils (EOs) on them were investigated in normal rats. The results showed that the pharmacokinetic parameters (AUC 0 - t , AUC 0 - ∞ , t 1/2 , t max , c max ) of the aforementioned compounds were significantly changed after co-administering with ZLNS EO. The AUC values of oxypaeoniflorin, paeoniflorin, ferulic acid, and baohuoside I with EOs were decreased significantly. This is the first report for the comparative pharmacokinetic study of ZLNS bioactive components in normal rats, which may provide the basis for drug interaction study in vivo and insight into their clinical applications., (© 2021 John Wiley & Sons, Ltd.)

Context: Total Glucosides of Paeony (TGP) capsule possesses various hepatoprotective activities. No study is available concerning TGP's concentration-effect relationship on hepatoprotection., Objective: To establish a pharmacokinetics-pharmacodynamics (PK-PD) modelling on TGP capsule's hepatoprotection after a single oral administration in hepatic injury rats., Materials and Methods: Male Sprague-Dawley rats were divided into five groups ( n  = 6): control, model (hepatic injury), treated-H (2.82 g/kg), treated-M (1.41 g/kg), and treated-L (0.705 g/kg) groups. All treated groups rats were intragastrically administered a single dose. An LC-MS/MS method was applied to determine paeoniflorin (Pae) and albiflorin (Alb) in rat serum. The effects of single-dose TGP on serum alanine transaminase (ALT), aspartate transaminase (AST) and total bile acid (TBA) were evaluated in hepatic injury rats., Results: Single dose (2.82, 1.41, or 0.705 g/kg) TGP capsule could real-time down-regulate serum TBA but not ALT and AST in hepatic injury rats within 20 h. An inhibitory effect Sigmoid E max of PK-PD modelling was established using Pae and Alb as PK markers and serum TBA as effect index. Pharmacodynamic parameters were calculated. For treated-H, treated-M and treated-L group, respectively, E 0 were 158.1, 226.9 and 245.4 μmol/L for Pae, 146.1, 92.9 and 138.4 μmol/L for Alb, E max were 53.0, 66.0, and 97.1 μmol/L for Pae, 117.4, 249.7 and 60.0 μmol/L for Alb, and EC 50 were 9.3, 5.2 and 2.7 μg/mL for Pae, 2.3, 0.8, and 0.8 μg/mL for Alb., Discussion and Conclusions: Serum TBA is a sensitive effect index for TGP's single dose PK-PD modelling, and it is potential for further multi-dose studies of TGP' effect on hepatic injury. The study provides valuable information for TGP's mechanistic research and rational clinical application.

Context: Peimine and paeoniflorin can be combined for the treatment of cough in paediatrics. The interaction during the co-administration could dramatically affect the bioavailability of drugs., Objective: The interaction between peimine and paeoniflorin was investigated in this study., Materials and Methods: The pharmacokinetics of paeoniflorin (20 mg/kg) with or without the coadministration of peimine (5 mg/kg for 10 days before paeoniflorin) was orally investigated in Sprague-Dawley rats ( n  = 6). The group without the peimine was set as the control group. The metabolic stability of paeoniflorin was studied in rat liver with microsomes. The effect of peimine on the absorption of paeoniflorin was investigated with Caco-2 cell monolayers., Results: The C max (244.98 ± 10.95 vs. 139.18 ± 15.14 μg/L) and AUC (0- t ) (3295.92 ± 263.02 vs. 139.18 ± 15.14 h·μg/L) of paeoniflorin was increased by peimine. The t 1/2 was prolonged from 5.33 ± 1.65 to 14.21 ± 4.97 h and the clearance was decreased from 15.43 ± 1.75 to 4.12 ± 0.57 L/h/kg. Consistently, peimine increased the metabolic stability of paeoniflorin with rat liver microsomes with the increased t 1/2 (56.78 ± 2.62 vs. 26.33 ± 3.15 min) and the decreased intrinsic clearance (24.42 ± 3.78 vs. 52.64 ± 4.47 μL/min/mg protein). Moreover, the transportation of paeoniflorin was also inhibited by peimine as the efflux ratio decreased from 3.06 to 1.63., Discussion and Conclusions: Peimine increased the systemic exposure of paeoniflorin through inhibiting the activity of CYP3A4 and P-gp. These results provide a reference for further in vivo studies in a broader population.

Control of hyperglycemia and prevention of glucose reabsorption (glucotoxicity) are important objectives in the management of type 2 diabetes. This study deals with an oral combined dosage form design for two anti-diabetic drugs, sitagliptin and dapagliflozin using self-nanoemulsifying drug delivery systems (SNEDDS). The SNEDDS were developed using naturally obtained bioactive medium-chain/long-chain triglycerides oil, mixed glycerides and nonionic surfactants, and droplet size was measured followed by the test for antioxidant activities. Equilibrium solubility and dynamic dispersion experiments were conducted to achieve the maximum drug loading. The in vitro digestion, in vivo bioavailability, and anti-diabetic effects were studied to compare the representative SNEDDS with marketed product Dapazin ® . The representative SNEDDS containing black seed oil showed excellent self-emulsification performance with transparent appearance. Characterization of the SNEDDS showed nanodroplets of around 50-66.57 nm in size (confirmed by TEM analysis), in addition to the high drug loading capacity without causing any precipitation in the gastro-intestinal tract. The SNEDDS provided higher antioxidant activity compared to the pure drugs. The in vivo pharmacokinetic parameters of SNEDDS showed significant increase in C max (1.99 ± 0.21 µg mL -1 ), AUC (17.94 ± 1.25 µg mL -1 ), and oral absorption (2-fold) of dapagliflozin compared to the commercial product in the rat model. The anti-diabetic studies showed the significant inhibition of glucose level in treated diabetic mice by SNEDDS combined dose compared to the single drug therapy. The combined dose of sitagliptin-dapagliflozin using SNEDDS could be a potential oral pharmaceutical product for the improved treatment of type 2 diabetes mellitus.

Context: Tadehaginoside, an active ingredient isolated from Tadehagi triquetrum (Linn.) Ohashi (Leguminosae), exhibited various biological activities. However, the pharmacokinetics and tissue distribution which affect tadehaginoside's therapeutic actions and application remain elusive., Objective: To clarify the metabolism of tadehaginoside in vivo ., Materials and Methods: The pharmacokinetics and tissue distribution of tadehaginoside and its metabolite p -hydroxycinnamic acid (HYD) were investigated using LC-MS/MS. Pharmacokinetic parameters were determined in 10 Sprague-Dawley rats divided into two groups, the intravenous group (5 mg/kg) and the oral group (25 mg/kg). For the tissue-distribution study, 20 rats were intravenously given tadehaginoside (5 mg/kg) before the experiment ( n  = 4). Biological samples were collected before drug administration (control group) and after drug administration., Results: The linearity, accuracy, precision, stability, recovery and matrix effect of the method were well-validated and the results satisfied the requirements of biological sample measurement. Treatment with tadehaginoside via intragastric and intravenous administration, the calculated C max in rats was 6.01 ± 2.14 ng/mL and 109.77 ± 4.29 ng/mL, and T max was 0.025 ± 0.08 h and 0.08 h, respectively. The results indicated that the quick absorption of tadehaginoside was observed following intravenous administration, and tadehaginoside in plasma of rats with intragastric administration showed relatively low concentration may be due to the formation of its metabolite. Tissue-distribution study indicated that kidney and spleen were the major distribution organs for tadehaginoside in rats and there was no long-term accumulation in most tissues., Discussion and Conclusion: These results could provide clues for exploring the bioactivity of tadehaginoside based on its pharmacokinetic characteristics.

The purpose of this study is to develop a sensitive LC-MS-MS method to simultaneously quantify polydatin and its metabolite, resveratrol, for its application in a pharmacokinetic (PK) study and to determine polydatin hydrolysis by microflora. A Shimadzu UHPLC system coupled to an AB Sciex QTrap 4000 mass spectrometer was used for the analysis. Separation was achieved using an Acquity BEH C 18 column (2.1 × 50 mm) with acetonitrile and 0.1% formic acid as the mobile phases. Analysis was performed under negative ionization mode using the multiple reaction monitoring (MRM) approach. The method was linear in the range of 9.77-1250 nM for both resveratrol and polydatin with correlation coefficient values >0.99. Themethodhas been shown to be reproducible, with intra- and inter-day accuracy and precision ±10.4% of nominal values, for both analytes. The average extraction recovery rates were 81.78-98.3% for polydatin and 86.4-103.2% for resveratrol, respectively. Matrix effect was in the acceptable range (<15%). The analytes in plasma were found to be stable under bench-top, freeze-thaw, and storage (-4 °C) conditions. The metabolic studies showed that polydatin can be rapidly hydrolyzed by rat fecal S9 fractions and PK studies showed that both polydatin and resveratrol were exposed in the plasma and variable tissues. This novel UPLC-MS-MS method can quantify the levels of both polydatin and its major metabolite resveratrol in biological samples., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The present study investigated whether combined ingestion of green tea catechins (GTC) and monoglucosyl hesperidin (GHES) influences the pharmacokinetic parameters of polyphenols and serum triglycerides (TG). We conducted 2 randomized, controlled trials. Study 1: 8 healthy male subjects participated in a crossover study in which they ingested a test beverage containing GHES (0, 84, 168, or 336 mg GHES) with GTC, or 336 mg GHES without GTC. After ingestion, the pharmacokinetic changes in plasma hesperetin (HEP) and catechins were measured. Study 2: 36 healthy male and female subjects (mean age, 53 ± 2 years; mean BMI, 25.2 ± 0.5 kg m -2 ) were recruited for a double-blind, placebo-controlled study in which they ingested a test beverage containing 165 mg GHES with 387 mg GTC or a placebo beverage daily for 4 weeks. Fasting serum TG and other lipids and glucose metabolites were analyzed. Study 1 showed that the pharmacokinetics of HEP did not differ significantly between the 336 mg GHES without GTC treatment and the 168 mg GHES with GTC treatment. Study 2 showed that continuous ingestion of 165 mg GHES and 387 mg GTC for 4 weeks significantly decreased fasting serum TG levels compared with baseline values (change in TG, -30 ± 13 mg dl -1 , P = 0.040) in the intention-to-treat analysis. In conclusion, our findings suggest that GTC affects the oral bioavailability of GHES, and combined ingestion of low doses of GHES with GTC effectively improves fasting TG levels.

The pharmacokinetics of compounds comprising hesperetin-7-glucoside with β-cyclodextrin and physically mixed hesperidin/dextrin was compared in 8 healthy adult male subjects in a nonrandomized, double-blind, cross-over, controlled study. For 0-24 h, the area under the curve of the total plasma hesperetin concentration after hesperetin-7-glucoside with β-cyclodextrin consumption was >100-fold higher than that after hesperidin/dextrin consumption., (© The Author(s) 2021. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

Resveratrol (RSV) and polydatin (PD) have been widely used to treat several chronic diseases, such as atherosclerosis, pulmonary fibrosis, and diabetes, among several others. However, their low solubility hinders their further applications. In this work, we show that the solubility of PD can be boosted via its co-crystallization with L-proline (L-Pro). Two different phases of co-crystals, namely the RSV-L-Pro (RSV:L-Pro = 1:2) and PD-L-Pro (PD:L-Pro = 1: 3), have been prepared and characterized. As compared to the pristine RSV and PD, the solubility and dissolution rates of PD-L-Pro in water (pH 7.0) exhibited a 15.8% increase, whereas those of RSV-L-Pro exhibited a 13.8% decrease. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of pristine RSV, PD, RSV-L-Pro, and PD-L-Pro against lung cancer cell line A549 and human embryonic kidney cell line HEK-293 indicated that both compounds showed obvious cytotoxicity against A549, but significantly reduced cytotoxicity against HEK-293, with PD/PD-L-Pro further exhibiting better biological safety than that of RSV/RSV-L-Pro. This work demonstrated that the readily available and biocompatible L-Pro can be a promising adjuvant to optimize the physical and chemical properties of RSV and PD to improve their pharmacokinetics.

In response to hypoxic-ischemic brain damage (HIBD), microglia activation and its mediated inflammation contribute to neuronal damage. Inhibition of over-activated microglia is deemed to be a potential therapeutic strategy. Our previous studies showed that gastrodin efficiently depressed the neuroinflammation mediated by activated microglia in HIBD neonatal rats. The underlying mechanisms through which gastrodin acts on activated microglia have not been fully elucidated. This study is designed to determine whether gastrodin would regulate the Notch signaling pathway and Sirtuin3 (Sirt3), which are implicated in regulating microglia activation. The present results showed that gastrodin markedly suppressed the expression of members of Notch signaling pathway (Notch-1, NICD, RBP-JK and Hes-1) in activated microglia both in vivo and in vitro. Conversely, Sirt3 expression was enhanced. In BV-2 microglia treated with a γ-secretase inhibitor of Notch pathway- DAPT, the expression of RBP-JK, Hes-1, and NICD was suppressed in activated microglia. Treatment with DAPT and gastrodin further decreased NICD and Hes-1 expression. Sirt3 expression was also decreased after DAPT treatment. However, Sirt3 expression in activated BV-2 microglia given a combined DAPT and gastrodin treatment was not further increased. In addition, combination of DAPT and Gastrodin cumulatively decreased tumor necrosis factor-α (TNF-α) expression. The results suggest that gastrodin regulates microglia activation via the Notch signaling pathway and Sirt3. More importantly, interference of the Notch signaling pathway inhibited Sirt3 expression, indicating that Sirt3 is a downstream gene of the Notch signaling pathway. It is suggested that Notch and Sirt3 synergistically regulate microglia activation such as in TNF-α production., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Background Sodium-glucose cotransporter 2 inhibitors reduce hospitalizations for heart failure and cardiovascular death, although the underlying mechanisms have not been resolved. The SIMPLE trial (The Effects of Empagliflozin on Myocardial Flow Reserve in Patients With Type 2 Diabetes Mellitus) investigated the effects of empagliflozin on myocardial flow reserve (MFR) reflecting microvascular perfusion, in patients with type 2 diabetes mellitus at high cardiovascular disease risk. Methods and Results We randomized 90 patients to either empagliflozin 25 mg once daily or placebo for 13 weeks, as add-on to standard therapy. The primary outcome was change in MFR at week 13, quantified by Rubidium-82 positron emission tomography/computed tomography. The secondary key outcomes were changes in resting rate-pressure product adjusted MFR, changes to myocardial flow during rest and stress, and reversible cardiac ischemia. Mean baseline MFR was 2.21 (95% CI, 2.08-2.35). There was no change from baseline in MFR at week 13 in either the empagliflozin: 0.01 (95% CI, -0.18 to 0.21) or placebo groups: 0.06 (95% CI, -0.15 to 0.27), with no treatment effect -0.05 (95% CI, -0.33 to 0.23). No effects on the secondary outcome parameters by Rubidium-82 positron emission tomography/computed tomography was observed. Treatment with empagliflozin reduced hemoglobin A 1c by 0.76% (95% CI, 1.0-0.5; P <0.001) and increased hematocrit by 1.69% (95% CI, 0.7-2.6; P <0.001). Conclusions Empagliflozin did not improve MFR among patients with type 2 diabetes mellitus and high cardiovascular disease risk. The present study does not support that short-term improvement in MFR explains the reduction in cardiovascular events observed in the outcome trials. Registration URL: https://clinicaltrialsregister.eu/; Unique identifier: 2016-003743-10.

Objectives: The aim of the study was to explore the effect of total glucosides of paeony (TGP) and Tripterygium wilfordii polyglycosides (TWP) on erythrocyte methotrexate polyglutamates (MTXPGs), the metabolites of methotrexate (MTX)., Methods: An ultra-high-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS) method was developed to determine MTXPGs. The effects of MTXPGs were analysed using 24 male Sprague-Dawley rats that were randomly divided into the MTX alone, MTX-TGP combined, and MTX-TWP combined groups. Rats were administered MTX at a dose of 0.9 mg/kg once a week, TGP at 0.054 g/kg and TWP at 1.8 mg/kg three times a day. Venous blood (1.0 ml) was collected at weeks 2, 4, 6, 9, 12 and 15 and then analysed using the developed UPLC-MS/MS method., Key Findings: Specificity, linear range, inter-and intra-day precision, recovery, matrix effect and stability of MTXPGs met the standard regulations. This method was successfully used for the detection of MTXPGs. After administration of MTX alone, erythrocyte MTXPGs increased and accumulated in a time- and dose-dependent manner. Compared to MTX alone, the combination with TGP significantly decreased the content of total MTXPGs and short-chain MTXPGs (Methotrexate [MTX/MTXPG1] and 4-amino-10-methylpteroyldiglutamic acid [MTXPG2], P < 0.05), but had no significant effect on long-chain MTXPGs (4-amino-10-methylpteroyltriglutamic acid [MTXPG3], P > 0.05) and very long-chain MTXPGs (4-amino-10-methylpteroyltetraglutamic acid [MTXPG4] and 4-amino-10-methylpteroylpentaglutamic acid [MTXPG5], P > 0.05) at week 15. The combination of MTX with TWP had no significant effect on the content of total MTXPGs, short-chain MTXPGs and long-chain MTXPGs (P > 0.05), but it significantly decreased the content of very long-chain MTXPGs (P < 0.05) at week 15., Conclusions: The UPLC-MS/MS method was successfully used to determine MTXPGs in rat erythrocytes. TGP and TWP in combination with MTX affected the production of MTXPGs of different chain lengths in erythrocytes., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Clinically, Wangbi Capsule (WBC) is widely used in the treatment of Rheumatoid arthritis (RA) because of its remarkable therapeutic effect. To reveal the mechanism, a pharmacokinetic-pharmacodynamic (PK-PD) model was developed for the first time to assess the relationship between time-concentration (dose)-effect. Freund's Complete Adjuvant was used to induce the adjuvant-induced arthritis model. Multi-indices were used to evaluate the therapeutic effect and an S-I max PK-PD model was established based on the concentrations of osthole, 5-O-methylvisamminoside, cimifugin, albiflorin, paeoniflorin and icariin and the levels of interleukin-1β and prostaglandin E 2 using a two-compartment PK model together with a PD model with an effect-site compartment. The results suggest that WBC can treat RA by regulating the levels of prostaglandin E 2 and interleukin-1β. For the PK-PD model, the parameters indicated that WBC had a large safety margin and all six bioactive ingredients of WBC have therapeutic effects on RA. Among them icariin, osthole and 5-O-methylvisamminoside may be the main effective substances. This study provided a scientific basis for further study of population pharmacokinetics / population pharmacodynamics (PPK/PPD), to develop a reasonable administration plan and improve individualized drug therapy., (© 2021 John Wiley & Sons, Ltd.)

Secoisolariciresinol diglucoside (SDG) is the principal lignan of flaxseed and precursor of its aglycone, secoisolariciresinol (SECO), and the mammalian lignans enterolactone (EL) and enterodiol (ED), the putative bioactive forms of oral administration of SDG. SDG is present in the seed hull as an ester-linked polymer. Although extraction and purification of SDG monomer is costly, the use of naturally occurring SDG in polymer form may offer a more economical approach for delivery of this precursor. The extent of SDG release from the polymer and subsequent bioavailability of SDG metabolites are unknown. To understand the relative bioavailability of SDG polymer, this study examined the comparative bioavailability of enriched SDG and SDG polymer in rats after a single oral SDG equivalent dose (40 mg/kg). A validated LC-MS/MS method quantified SDG and its metabolites in rat plasma following serial blood collections. SDG remained undetectable in rat plasma samples. Unconjugated SECO was detected in plasma after 0.25 h. Unconjugated ED was observed after 8 h (3.4 ± 3.3 ng/mL) and 12 h (6.2 ± 3.3 ng/mL) for enriched SDG and SDG polymer, respectively. Total (conjugated and unconjugated) ED and EL resulting from enriched SDG and SDG polymer reached similar maximal concentrations between 11 and 12 h and demonstrated similar total body exposures (AUC values). These data suggest a similar pharmacokinetic profile between the enriched and polymer form of SDG, providing support for the use of SDG polymer as a more economical precursor for SECO, ED, and EL in applications of chronic disease management.

Background: Patients with type 2 diabetes mellitus (T2DM) are characterized by an elevated glycemic index and are at a higher risk for complications such as cardiovascular disease, nephropathy, retinopathy and peripheral neuropathy. Normalization of glycemic index can be achieved by dosing combinations of metformin with other anti-diabetic drugs. The present study (Clintrials number NCT00519480) was conducted to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of remogliflozinetabonate, an SGLT2 inhibitor, withdoses (500 mg and 750 mg BID) greater than the commercial dose (100 mg BID)in combination with metformin with minimum daily dose of 2000 mg given in two divided doses., Methods: This was a randomized, double-blinded, repeat dose study in 50 subjects with T2DM. The study was conducted in three phases; run-in, randomization, and treatment. All subjects were on a stable metformin dosing regimen. Cohort 1 subjects were randomly allocated to receive either remogliflozin etabonate 500 mg BID or placebo BID (2:1) in addition to metformin. Cohort 2 subjects were administered with either remogliflozin etabonate 750 mg BID or placebo BID (2:1) in addition to metformin for 13 days. All the subjects were assessed for safety (adverse events, lactic acid levels, vital signs, electrocardiogram [ECG]), pharmacokinetic evaluation, and pharmacodynamics (Oral Glucose Tolerance Testing) parameters., Results: Co-administration of remogliflozin etabonate and metformin was well tolerated in all subjects during the observation period. There were no severe or serious adverse events (SAEs) and no increase in lactic acid concentration was reported during the study. The statistical results showed that concomitant administration of remogliflozin etabonate, either 500 mg or 750 mg BID, with metformin had no effect on the pharmacokinetics of metformin. The accumulation ratios, Day 13 vs. Day 1, for AUC values of remogliflozin etabonate and its metabolites were all very close to 1, indicating no accumulation in plasma concentrations of remogliflozin etabonate and its metabolites. Mean glucose values from baseline and glucose and insulin values following oral glucose tolerance test (OGTT) were decreased in all treatment groups., Conclusion: Co-administration of doses of remogliflozin etabonate (500 mg BID or 750 mg BID) greater than the commercial dose (100 mg BID) with metformin (2000 mg BID) was shown to be safe and effective during the observation period., Trial Registration: ClinicalTrials.gov , NCT00519480 . Registered:22 August 2007.

Purpose: Combination therapy with insulin-independent sodium-glucose cotransporter 2 inhibitors and thiazolidinedione drugs, such as lobeglitazone, has been reported to elicit potential additive efficacy in glycemic control in type 2 diabetes mellitus. This study was conducted to evaluate the pharmacokinetic (PK) drug-drug interactions between empagliflozin and lobeglitazone in healthy subjects., Subjects and Methods: A randomized, open-label, multiple-dose study was conducted in 30 healthy subjects using a three-treatment, six-sequence, three-way crossover design. Subjects received one of the following treatments once daily for 5 days in each period: 25 mg empagliflozin, 0.5 mg lobeglitazone sulfate, or a combination. Serial blood sampling before every dose and up to 24 h after the last dose was performed during each treatment period. The PK parameters were estimated using noncompartmental methods with the plasma empagliflozin and lobeglitazone concentrations. The absence of a PK interaction was construed as the 90% confidence interval (90% CI) of maximum concentration at steady state (C max,ss ) and area under the concentration-time curve over the dosing interval (AUC tau ) for combination therapy-to-monotherapy ratios within the limits of 0.80-1.25., Results: The steady-state plasma empagliflozin and lobeglitazone concentration-time profiles of combination therapy and monotherapy were comparable in the 25 subjects who completed the study. Coadministration of empagliflozin with lobeglitazone did not affect empagliflozin PK (with 90% CIs of 0.956-1.150 and 0.945-1.133 for C max,ss and AUC tau , respectively). Likewise, empagliflozin did not affect lobeglitazone C max,ss or AUC tau (with 90% CIs of 0.869-0.995 and 0.851-1.018, respectively). All treatment groups tolerated mild adverse events well., Conclusion: The lack of PK interactions between lobeglitazone and empagliflozin in combination therapy, along with their good tolerability, indicates that the two drugs can be coadministered without dose adjustment., Trial Registration Number: NCT02854748, Registered on August 7, 2016., Competing Interests: The authors report no conflicts of interest in this work., (© 2021 Kim et al.)

Background: Huangqi decoction (HQD) has been used to treat chronic liver diseases since the 11th century, but the effective components in HQD against liver fibrosis have not been definitively clarified., Purpose: To investigate and identify multiple effective components in HQD against liver fibrosis using a pharmacokinetics-based comprehensive strategy., Methods: The absorbed representative components in HQD and their metabolites were detected in human plasma and urine using high-resolution mass spectrometry combined with a database-directed method, and then pharmacokinetics in multiple HQD components in human plasma was analyzed by ultra-performance liquid chromatography coupled with triple-quadruple mass spectrometry. Furthermore, the anti-fibrotic effect of potential effective HQD components was studied in LX-2 cells and that of a multi-component combination of HQD (MCHD) was verified in a mouse CCl 4 -induced hepatic fibrosis model., Results: Twenty-four prototype components in HQD and 17 metabolites were identified in humans, and the pharmacokinetic characteristics of 14 components were elucidated. Among these components, astragaloside IV, cycloastragenol, glycyrrhizic acid, glycyrrhetinic acid, liquiritigenin, and isoliquiritigenin downregulated the mRNA expression of α-SMA; cycloastragenol, calycosin-7-O-β-D-glucoside, formononetin, glycyrrhetinic acid, liquiritin, and isoliquiritin downregulated the mRNA expression of Col I; and calycosin, liquiritigenin, isoliquiritigenin, cycloastragenol, and glycyrrhetinic accelerated the apoptosis of LX-2 cells. MCHD reduced serum aminotransferase activity and hepatic collagen fibril deposition in mice with CCl 4 -induced hepatic fibrosis., Conclusion: Using the pharmacokinetics-based comprehensive strategy, we revealed that multiple effective HQD components act together against liver fibrosis., (Copyright © 2021. Published by Elsevier GmbH.)

Isoliquiritigenin (ILG) and isoliquiritin (ILQ), two kinds of major flavonoids in licorice, are biological active substances with antioxidant, anti-inflammatory, and tumor-suppressive effects. However, their in vivo metabolites, possible material basis of this two licorice chalcones for the treatment of diseases, have not been studied completely. To determine the metabolism of ILG and ILQ, after oral administration of 100 mg/kg/day of these compounds for consecutive 8 days, the metabolites of these two licorice chalcones in mice plasma, urine, feces, and bile were determined using liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry in this study. The structures of those metabolites were tentatively identified according to their fragment pathways, accurate masses, characteristic product ions, metabolism law, and reference standards-matching. As a result, a total of 25 and 29 metabolites of ILG and ILQ were identified, respectively. Seven main metabolic pathways, oxidation and reduction, deglycosylation and glycosylation, dehydroxylation and hydroxylation, demethoxylation and methoxylation, acetylation, glucuronidation, and sulfation, were summarized to tentatively explain how the metabolites were biologically transformed. These results provide the important information on the metabolism of ILG and ILQ, which may be helpful for the further research of their pharmacological mechanism., (© 2020 John Wiley & Sons, Ltd.)

This analysis reports a quantitative modeling and simulation approach for oral dapagliflozin, a primarily uridine diphosphate-glucuronosyltransferase (UGT)-metabolized human sodium-glucose cotransporter 2 selective inhibitor. A mechanistic dapagliflozin physiologically based pharmacokinetic (PBPK) model was developed using in vitro metabolism and clinical pharmacokinetic (PK) data and verified for context of use (e.g., exposure predictions in pediatric subjects aged 1 month to 18 years). Dapagliflozin exposure is challenging to predict in pediatric populations owing to differences in UGT1A9 ontogeny maturation and paucity of clinical PK data in younger age groups. Based on the exposure-response relationship of dapagliflozin, twofold acceptance criteria were applied between model-predicted and observed drug exposures and PK parameters (area under the curve and maximum drug concentration) in various scenarios, including monotherapy in healthy adults (single/multiple dose), monotherapy in hepatically or renally impaired patients, and drug-drug interactions with UGT1A9 modulators, such as mefenamic acid and rifampin. The PBPK model captured the observed exposure within twofold of the observed monotherapy data in adults and adolescents and in special population. As a guide to determining dosing regimens in pediatric studies, the verified PBPK model, along with UGT enzyme ontogeny maturation understanding, was used for predictions of dapagliflozin monotherapy exposures in pediatric subjects aged 1 month to 18 years that best matched exposure in adult patients with a 10-mg single dose of dapagliflozin., (© 2021 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

We describe the dramatic differences in the synthesis and physiological and pharmacokinetical profiling of two sodium-glucose cotransporter (SGLT) drug candidates AVE2268 and AVE8887 with very similar chemical structures. It is a classic example of how a radioactive study was able to spare resources in preclinical development prior to entering a costly clinical program. It also demonstrated that radioactive compounds can be used to study differences between two very similar compounds in vivo., (© 2020 John Wiley & Sons, Ltd.)

Forsythin extracted from Forsythiae Fructus is widely used to treat fever caused by the common cold or influenza in China, Japan and Korea. The present study aimed to analyze the pharmacokinetics, metabolism and excretion routes of forsythin in humans and determine the major enzymes and transporters involved in these processes. After a single oral administration, forsythin underwent extensive metabolism via hydrolysis and further sulfation. In total, 3 of the 13 metabolites were confirmed by comparison to reference substances, i.e., aglycone M1, M1 sulfate (M2), and M1 glucuronide (M7). Hydrolysis was the initial and main metabolic pathway of the parent compound, followed by extensive sulfation to form M2 and a reduced level of glucuronidation to form M7. In addition, the plasma exposure of M2 and M7 were 86- and 4.2-fold higher than that of forsythin. Within 48 h, ~75.1% of the administered dose was found in urine, with M2 accounting for 71.6%. Further phenotyping experiments revealed that sulfotransferase 1A1 and UDP-glucuronosyltransferase 1A8 were the most active hepatic enzymes involved in the formation of M2 and M7, respectively. The in vitro kinetic study provided direct evidence that M1 showed a preference for sulfation. Sulfated conjugate M2 was identified as a specific substrate of organic anion transporter 3, which could facilitate the renal excretion of M2. Altogether, our study demonstrated that sulfation dominated the metabolism and pharmacokinetics of forsythin, while the sulfate conjugate was excreted mainly in the urine.

Background: To understand the cumulative effect of topical formulations after medication, evaluate the therapeutic effect of microneedle-assisted (MN-assisted) paeoniflorin-loaded ethosomes (TGP-E), and explore the potential for deep penetration of drugs, this paper uses microdialysis to systematically study the percutaneous pharmacokinetics of TGP-E., Methods: First, optical coherence tomography (OCT) was used to study the effectiveness of microneedle puncture. Second, a microdialysis method and a UPLC-MS method for determining the amount of paeoniflorin (Pae) in dialysate were established. Finally, the transdermal pharmacokinetics of TGP-E was studied using in vivo microdialysis in rats under the above MN-assisted conditions., Results: The optimal MN-assisted conditions were obtained at a microneedle length of 500 μm, a pressure of 3 N, and an action time of 3 min. The pharmacokinetic results demonstrated that the maximum drug concentration (Cmax) and the area under the curve (AUC) of the TGP-E gel were higher than the TGP-saline solution gel, and the mean retention time was lower. These indicated that microneedle can promote the entry of the ethosomes into the skin for in vivo experiments and greatly improve the possibility of deep penetration of the water-soluble Pae., Conclusion: Therefore, the microneedle-ethosomes delivery system is a more ideal means for promoting the deep penetration of Pae. These findings may provide a reference for the combination of multiple penetration-enhancement ways to promote drug absorption, and also provide a new insight to realize the development of novel, safe, and more effective dosage forms and administration routes of drugs., (© 2021 S. Karger AG, Basel.)

Raw Moutan Cortex (RMC) and Processed Moutan Cortex (PMC) have a long history of use in China and other Asian countries. In this study, a rapid and accurate ultra-high-pressure liquid chromatography coupled with diode array detector (UHPLC-DAD) method was developed and validated for the simultaneous determination of nine absorbed compounds of RMC/PMC. After extraction by protein precipitation with methanol from plasma, the analytes were separated on an Acquity UPLC® BEH Shield RP 18 column (2.1 × 100 mm, 1.7 μm, Waters, USA). Acetonitrile (A) and 0.1% (v/v) formic acid in water (B) were selected as the mobile phase to perform gradient elution. The linearity of nine analytes was >0.9915. The intra- and inter-assay precision (RSD) values were within 11.18%, and accuracy ranged from 91.32 to 101.29%. Suitable stability, matrix effect and extraction recoveries were also obtained. The validated method was applied to compare the pharmacokinetics of RMC and PMC in Blood-Heat and Hemorrhage Syndrome Model and normal rats. The results revealed that processing and the pathological state could influence the pharmacokinetic characteristics of compounds in RMC/PMC. The study willbe useful for further studies on pharmacokinetics and clinical application of raw and processed Moutan Cortex., (© 2020 John Wiley & Sons, Ltd.)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) effectively lower plasma glucose (PG) concentration in patients with type 2 diabetes, but studies have suggested that circulating glucagon concentrations and endogenous glucose production (EGP) are increased by SGLT2i, possibly compromising their glucose-lowering ability. To tease out whether and how glucagon may influence the glucose-lowering effect of SGLT2 inhibition, we subjected 12 patients with type 2 diabetes to a randomized, placebo-controlled, double-blinded, crossover, double-dummy study comprising, on 4 separate days, a liquid mixed-meal test preceded by single-dose administration of either 1 ) placebo, 2 ) the SGLT2i empagliflozin (25 mg), 3 ) the glucagon receptor antagonist LY2409021 (300 mg), or 4 ) the combination empagliflozin + LY2409021. Empagliflozin and LY2409021 individually lowered fasting PG compared with placebo, and the combination further decreased fasting PG. Previous findings of increased glucagon concentrations and EGP during acute administration of SGLT2i were not replicated in this study. Empagliflozin reduced postprandial PG through increased urinary glucose excretion. LY2409021 reduced EGP significantly but gave rise to a paradoxical increase in postprandial PG excursion, which was annulled by empagliflozin during their combination (empagliflozin + LY2409021). In conclusion, our findings do not support that an SGLT2i-induced glucagonotropic effect is of importance for the glucose-lowering property of SGLT2 inhibition., (© 2020 by the American Diabetes Association.)

Acteoside is one of the most widespread phenylethanoid glycosides with pharmacological activities, including antioxidant, neuroprotective property, etc. However, its bioavailability is poor due to the low absorption and P-gp efflux. This study aimed to select food derived P-gp inhibitors for promoting the acteoside absorption and investigate whether the inhibitors could increase the bioavailability and stability of acteoside. Results showed that EGCG and quercetin significantly decreased the BL-to-AP efflux and promoted the AP-to-BL influx of acteoside across Caco-2 monolayers with optimum concentrations of 320 μM EGCG or 240 μM quercetin adding to 320 μM acteoside. EGCG increased the bioavailability of acteoside to 1.43-fold, but quercetin had no such effect. Further study showed that EGCG and quercetin had no effects on the storage and digestion stability of acteoside. This work revealed that EGCG could improve the acteoside absorption across the Caco-2 monolayers and enhance the bioavailability of acteoside in rats., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Yazhangsan (YZS) is a common prescription for the treatment of cough and asthma caused by wind-cold. The purpose of this study was to investigate the pharmacokinetic profiles of 10 bioactive components in YZS. A simple, sensitive and reliable high-performance liquid chromatography coupled with a triple-quadruple mass spectrometry method (LC-MS/MS) was developed and fully validated in this study for the measurement of these 10 bioactive compounds in rat plasma. One-step protein precipitation method using methanol was applied to the treatment of rat plasma samples. Chromatographic separation was conducted on a C 18 column by gradient elution, and water (containing 0.1% formic acid) and acetonitrile were chosen as the mobile phase. The analytes were quantified by using a mass spectrometer in multiple reaction monitoring scanning mode, and electrospray ionization was performed in positive and negative ion modes. The established method met the requirements for the quantification of these 10 bioactive compounds in biological samples, and it was successfully applied to the pharmacokinetic study of 10 components in rats after the intragastrical administration of YZS. This study will lay a foundation for the investigation of the mechanism of action of YZS and provide useful data for the rational use of YZS in clinical., (© 2020 John Wiley & Sons, Ltd.)

Traditional Chinese medicine was widely used in China since its definite effects and therapy. The components of TCM were absorbed into the circle system as the format of prototypes or metabolites, which contributed to the therapy or side effects. Declaring the functional changes in this process was of great importance to the clinical applications. In this work, an integrated strategy based on metabolites' profiling and network pharmacology was proposed for exploring the pharmacological changes of compounds in vivo. Arctiin, the main component in Fructus Arctii with various kinds of bioactivities, was used as an example. An ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry and metabolynx™software was applied to characterize the metabolites of arctiin in rats at a dosage of 100 mg/kg; network pharmacology was applied to characterize the functional changes. As a result, fifty-three metabolites (32 in plasma, 40 in urine, 19 in bile, 20 in feces, 1 in brain, 12 in liver and 4 in lungs) were screened out and characterized, and 3 of them were unambitiously identified by comparison with standard substances. Among them, 38 metabolites were reported for the first time. It was found the major metabolic pathways of arctiin in rats were demethylation, lactone-opening and phase II conjugations with sulfate and glucuronide.It also confirmed that M14, M15, M18, M23, M22, M43 and M45 were the major circulating forms of arctiin in rats following oral administration. In addition to the above metabolic reactions, phase I reactions of hydrolysis, demethylation, dehydroxylation were also observed, and dehydrogenation were first revealed metabolic patterns of arctiin in rats. Meanwhile, in addition to the main targets of arctiin (MTOR, EGFR and MAPK14), its metabolites targeted additional 392 targets with additional functions of anti-hepatitis B or viral carcinogenesis (SRC, CAPS3, PIK3CA, CDK4, ESR1, MMP9 and ERBB2). The above results provided very important information for understanding the metabolism and functional changes of arctiinin vivo, and supporting data for further pharmacological evaluation. Our work also provided a newsight for elucidation of functional changes of TCMs in vivo., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)