Pharmacokinetics and Bioequivalence Comparison of Two Fixed-Dose Combination of Rosuvastatin/Ezetimibe Formulations: A Randomized, Crossover, Open-Label Study in Healthy Volunteers

Objective: To evaluate the bioequivalence (BE) of two fixed-dose combination (FDC) formulations of Rosuvastatin and Ezetimibe: Cresadex® EZE 20/10 mg (Abbott Laboratories) as the reference formulation (R), and Racor® Duo 20/10 mg (Laboratorios Leti, S.A.V.) as the test formulation (T). Method: A randomized, single-dose, two-period, two-sequence, open-label, crossover design was employed. Subjects received a single oral dose of either the Test or Reference formulation under fasting conditions, with a 12-day washout period between treatments. Male subjects aged 18 - 45 years with normal health and laboratory values were included. Exclusion criteria encompassed any medical conditions, recent surgery, drug or alcohol use, and hypersensitivity to the study drugs. Blood samples were collected at pre-dose and multiple post-dose time points and analyzed using a validated LC-MS/MS method to quantify Rosuvastatin and Ezetimibe concentrations in plasma. Descriptive statistics were used to summarize pharmacokinetic (PK) parameters. ANOVA was conducted to compare the ln-transformed values of Cmax, AUC0−t, and AUC0−∞. Schuirmann’s two one-sided t-tests were applied to assess bioequivalence (BE). Results: The 90% Confidence Intervals for the ln-transformed ratios of Cmax, AUC0−t, and AUC0−∞ fell within the acceptance range of 80% to 125%, demonstrating bioequivalence between the Test and Reference formulations. Both formulations were well-tolerated, with no serious adverse events reported. Conclusions: The results of this study confirm the bioequivalence of the two tested FDC Rosuvastatin/Ezetimibe formulations: Cresadex® EZE (Abbott Laboratories) and Racor® Duo (Laboratorios Leti, S.A.V.). These findings endorse the therapeutic interchangeability of these products, providing clinicians with greater flexibility in the treatment of hyperlipidemia.

Pharmacokinetics and Bioequivalence Evaluation of Two Rosuvastatin Calcium 20 mg Tablets: A Single Oral Dose, Randomized-Sequence, Open-Label, Two-Period Crossover Study in Healthy Volunteers under Fasting Conditions

Objectives: To compare the rate and extent of absorption of Racor® 20 mg (Rosuvastatin calcium 20 mg) tablet of Laboratorios Leti, S.A.V., with Crestor® 20 mg (Rosuvastatin calcium 20 mg) tablet of AstraZeneca, UK Limited in healthy adult human subjects under fasting conditions. Method: This was an open label, analyst blind, balanced, randomized, two-treatment, two-period, two-sequence, single oral dose, crossover, bioequivalence study in healthy, adult, human subjects under fasting condition. Twenty-four (24) subjects were planned as per the protocol and all subjects completed both periods of the study. The concentrations of Rosuvastatin in plasma were quantitated using a validated LC-MS/MS method of analysis and plasma levels were submitted for statistical analysis. Cmax, AUC0-t, AUC0-∞, Tmax, t1/2, Kel (hrs-1), percent AUC extrapolated [100 * (AUC0-∞ - AUC0-t)/AUC0-∞] (AUC_%Extrapobs) were calculated for rosuvastatin in plasma using SAS® version 9.1.3, SAS Institute. Inc. USA.CARY. ANOVA, 90% confidence interval using Schuirmann’s two one-sided test for bioequivalence, power and ratio analysis, for lntransformed pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ were computed and reported for Rosuvastatin in plasma for BE. Results: Data showed that 90% confidence intervals for the test/reference geometric mean ratios (GMR) of Cmax (95.01 - 112.66), AUC0-t (93.38 - 111.67) and AUC0-∞ (93.65 - 111.29) were within the BE (80% - 125%) acceptance range. Conclusions: Two products formulation, reference (R) Crestor® (rosuvastatin calcium) of AstraZeneca and test (T), Racor® (rosuvastatin calcium) of Laboratorios Leti S.A.V., with a single dose of 20 mg, under fasting conditions were bioequivalent. No severe, serious or unexpected adverse events (AEs) were reported in this study.

Gut microbiota-mediated metabolism of Panax notoginseng saponins and its role in pharmacokinetics and pharmacodynamics

Panax notoginseng saponins(PNS)are a class of effective ingredients in Notoginseng Radix et Rhizoma,a well-known herbal medicine called San-Qi in Chinese.After oral administration,PNS inevitably interacts with gut microbiota,and thus affect the pharmacokinetic profiles and pharmacological effects.To date,studies concering gut microbiota-mediated metabolism of PNS have not been reviewed systematically.Herein,we outline the metabolic profiles of Panax notoginseng saponins mediated by gut microbiota,as well as its role in the pharmacokinetics and pharmacodynamics on the basis of reported data.The metabolic pathways of primary saponins are proposed,and step-by-step deglycosylation is found to be the primary degradation pathways of PNS mediated by gut microbiota.Specific microorganisms and enzymes involved in the metabolic processes were summarized.Gut microbiota is deeply involved in the metabolism of PNS,affects the pharmacokinetic profiles,and produces a series of active metabolites.These metabolites were documented to play an essential role in the efficacy of the parent compounds.Future studies should focus on strengthening the real-world evidence,defining the interaction between gut microbiota and PNS,and developing the strategy for modulating gut microbiota to enhance the bioavailability and efficacy of PNS.These information would be useful for further research and clinical application of PNS.

GC-MS/MS Method for Determination and Pharmacokinetics of Main Components of Cang-Ai Volatile Oil in Rat Plasma after Intravenous Administration

[Objectives]To establish a gas chromatography-triple quadrupole mass spectrometry(GC-MS/MS)method based on multiple reaction monitoring(MRM)mode for the analysis of the major components in Cang-ai volatile oil(CAVO).[Methods]An ultrasensitive gas chromatography-tandem mass spectrometry(GC-MS/MS)method was developed and validated for the determination of three highly abundant components in rat plasma samples.Paeonol was used as an internal standard.A multiple reaction monitoring(MRM)model was employed for the quantification of the three major components of CAVO.[Results]The method demonstrated linearity over the range of 0.25 to 50μg/mL with a correlation coefficient(R 2)greater than 0.9998.The lower limit of quantification was 0.25μg/mL.Intra-day and inter-day accuracy and precision were within 15%.Extraction recovery and matrix effect values ranged from 90.1%to 110.6%and 0.1%to 2.1%,respectively.[Conclusions]This method was successfully applied to the simultaneous determination of the three components in high-level CAVO plasma samples,providing a basis for subsequent studies of CAVO.

Pharmacokinetics of Gelsemium elegans in female rats

Background:Gelsemium elegans Benth(G.elegans)is a poisonous perennial evergreen vine plant that has been applied in livestock production and veterinary clinical practice.Early studies found that the toxicity of G.elegans showed significant gender differences in rats,but the underlying reasons for this difference are still not well understood.Methods:In order to explore whether the gender differences in the toxicity of G.elegans are related to pharmacokinetic differences,based on the previous pharmacokinetic study of multiple components of G.elegans in male rats,this study used HPLC-MS/MS method established in the laboratory to conduct a pharmacokinetic study of multiple alkaloids in the plasma of female rats after a single gavage administration of G.elegans(dose of 0.1 g/kg).Results:Through detection,17 alkaloid components in the plasma of female rats were identified,and the pharmacokinetic parameters of 11 of these alkaloids were calculated.We find that in female rats.The T_(max)values were generally less than 0.5 h,and the T_(1/2)values exceeded 3 h,with the longest reaching up to 32.80 h half elimination time.Additionally,the C_(max)and AUC results indicated that female rats had generally higher absorption and exposure levels for most alkaloids.Conclusion:These results suggest that the reason for the differences in the toxicology of G.elegans may be related to the absorption and exposure of gelsemidine-type alkaloids in animals.

Pharmacokinetics of Enrofloxacin and Its Metabolite in Carp (Cyprinus carpio) After a Single Oral Administration in Medicated Feed

A precise and reliable analytical method of high performance liquid chromatography-tandem mass spectrometry(HPLCMS/MS)was developed to measure trace levels of enrofloxacin(ENR)and its major metabolite ciprofloxacin(CIP)in carp tissues.Optimized chromatographic separation was obtained on a Waters Xterra MS C_(18) reversed-phase column using gradient elution with methanol and 0.1%formic acid aqueous solution including 5mmolL^(-1) of ammonium acetate.The established method was applied to study the pharmacokinetics and distribution of ENR and CIP in tissues of carp following a single oral administration in feed at a dosage of 40mgkg^(-1) bw(body weight).Data were analyzed using DAS 2.0 dynamics software,and the experimental results suggest that ENR was rapidly absorbed and extensively distributed in carp tissues through systemic circulation,and the pharmacokinetic characteristics can be described with a two-compartment model.The elimination half-lives(t_(1/2β))from muscle,liver,gill,plasma and skin were 131,160,104,132 and 310 h,respectively.The areas under the drug concentration-time curves(AUC)for these tissues were 491,972,750,249 and 706hmgkg^(-1),respectively.The maximum concentration(C_(max))values were 13,29,37,9 and 5mgkg^(-1) with peak times(t_(max))of 8,4,4,2 and 4 h,respectively.Ciprofloxacin,the active metabolite of ENR,was also detected in carp tissues,indicating that only 1.54%of de-ethylation of ENR occurs in carp.At a water temperature of 18℃,the drug withdrawal time was determined to be no less than 24 d while the carp was fed at a single dosage of 40mgkg^(-1).

Eight Zhes Decoction ameliorates the lipid dysfunction of nonalcoholic fatty liver disease using integrated lipidomics, network pharmacology and pharmacokinetics

Nonalcoholic fatty liver disease(NAFLD)has developed into the most common chronic liver disease and can lead to liver cancer.Our laboratory previously developed a novel prescription for NAFLD,“Eight Zhes Decoction”(EZD),which has shown good curative effects in clinical practice.However,the pharmacodynamic material basis and mechanism have not yet been revealed.A strategy integrating lipidomics,network pharmacology and pharmacokinetics was used to reveal the active components and mechanisms of EZD against NAFLD.The histopathological results showed that EZD attenuated the degrees of collagen deposition and steatosis in the livers of nonalcoholic steatofibrosis model mice.Furthermore,glycerophospholipid metabolism,arachidonic acid metabolism,glycerolipid metabolism and linoleic acid metabolism with phospholipase A2 group IVA(PLA2G4A)and cytochrome P450 as the core targets and 12,13-cis-epoxyoctadecenoic acid,12(S)-hydroxyeicosatetraenoic acid,leukotriene B4,prostaglandin E2,phosphatidylcholines(PCs)and triacylglycerols(TGs)as the main lipids were found to be involved in the treatment of NAFLD by EZD.Importantly,naringenin,artemetin,canadine,and bicuculline were identified as the active ingredients of EZD against NAFLD;in particular,naringenin reduces PC consumption by inhibiting the expression of PLA2G4A and thus promotes sufficient synthesis of very-low-density lipoprotein to transport excess TGs in the liver.This research provides valuable data and theoretical support for the application of EZD against NAFLD.

Pharmacokinetics of fucoidan and low molecular weight fucoidan from Saccharina japonica after oral administration to mice

The brown seaweed,Sacchairna japonica,has been used in traditional Chinese medicine for over one thousand years.Oral administration of fucoidan or low molecular weight fucoidan(LMWF)from S.japonica could ameliorate kidney dysfunction in chronic kidney diseases and inhibit diabetic vascular complications.In many studies,LMWF was found to be more potent than fucoidan with high molecular weight.However,the pharmacokinetics of LMWF still remains unclear.The purpose of the research is to compare the pharmacokinetics of fucoidan with high molecular weight(136 kDa)with that low molecular weight(9.5 kDa)after oral administration to ICR mice.Since fucose is the main and representative monosaccharide of fucoidans,we evaluate the pharmacokinetics of fucoidan and LMWF by determining the fucose concentration in mice serum.Both fucoidan and LMWF were absorbed following oral administration.Fucoidan and LMWF were provided to mice by oral administration with 60 mg/kg and the maximum Concentration(C_(max))was found at 2.5 h(0.66±0.32 mg/L)for Fucoidan and 1.5 h(1.01±0.56 mg/L)for LMWF,respectively.It seems that LMWF had a higher area under the curve(AUC_(0–t))and was absorbed more quickly than fucoidan.The estimated bioavailability of LMWF was28.3%in the mice treated with a single dose of 30 mg/kg.In addition,LMWF was found widely spreaded into different tissues following oral administration and the highest concentration was found in kidney at 19.93±7.02μg/g.In this study,we first studied the pharmacokinetics of LMWF,in order to help to understand the function of LMWF.And our results shed light on the potential of development of drugs based on LMWF.

DFT-Based Chemical Reactivity Descriptors, Pharmacokinetics and Molecular Docking Studies of Thymidine Derivatives

Thymidine-containing derivatives are considered to be among the most significant derivatives in medicinal chemistry. In this study, we employed a combined computational approach involving density-functional theory (DFT) calculations, molecular docking simulations, and absorption, distribution, metabolism, excretion, and toxicity (ADMET) property predictions. Prediction of activity spectra for substances (PASS) revealed promising antiviral, antimicrobial and anti-carcinogenic activities of these thymidine derivatives. Using Gaussian 09, we optimized the molecular structures of the thymidine derivatives to obtain their stable conformations and calculate their electronic properties. Subsequently, molecular docking simulations were performed to explore the binding interactions between the thymidine derivatives and the active site of the Candida albicans (PDB: 1IYL and 2Y7L) proteins. The docking results were evaluated based on docking scores, hydrogen bonding, and hydrophobic interactions and revealed favorable binding interactions between the thymidine derivatives and the proteins, suggesting their potential as antifungal agents. The thermodynamic properties, including binding free energy, enthalpy, and entropy changes were determined to assess the stability and strength of the ligands-protein complexes. The calculated pharmacokinetic parameters, such as ADMET properties, provided insights into the drug-likeness and potential bioavailability of the thymidine derivatives. These results offer a foundation for further experimental investigations and the design of novel antifungal agents targeting Candida albicans infections.

Pharmacokinetics of nitrogen-containing metabolites R-gentiandiol and S-gentiandiol in rat plasma after oral administration of swertiamarin

Objective:A chiral resolution method for enantiomers of two chiral nitrogen-containing metabolites R-gentiandiol and S-gentiandiol of swertiamarin in plasma was developed,and the pharmacokinetics of the metabolites were studied.Methods:The metabolites of swertiamarin in vivo were detected by LC-MS/MS using Astec CyclobondⅡCyclodextrin column(4.6 mm×100 mm,5μm),gradient elution with acetonitrile-water as mobile phase,and monitored by multiple reaction monitoring(MRM)method in positive mode.The ion pairs for quantitative analysis are R-gentiandiol(m/z 210.04→192.06),S-gentiandiol(m/z 210.04→192.06)and gentianone(m/z 192.02→162.08).Results:The linear correlation coefficients of the method developed were greater than 0.999,the precision was less than 7.00%,the recovery was 99.57%-102.65%,and the matrix effect was 90.94%-91.34%.The peak t_(max)of R-gentiandiol and S-gentiandiol in rat plasma after oral administration of swertiamarin were(1.63±0.23)h and(1.58±0.21)h,t_(1/2)was(6.23±0.52)h and(5.46±0.38)h,C_(max)was(86.79±20.81)ng/mL and(60.72±18.95)ng/mL,and the AUC_(0-24)were(1094.58±86.37))(ng·h)/mL and(724.67±58.38)(ng·h)/mL,respectively.Conclusion:The method was highly sensitive with good accuracy and precision,and it was successfully applied for chiral resolution and pharmacokinetics study of R-gentiandiol and S-gentiandiol in plasma.The method developed and experimental results will provide scientific basis for the study of pharmacodynamics and pharmacodynamic material basis of swertiamarin,and lay a foundation for clinical application and resource development of TCM monomer.

baicalin-Fe^(2+)络合染料的制备及对蚕丝织物的印花

为了缩短天然染料印花加工流程和提升印花产品品质,采用黄芩苷与亚铁离子发生配位反应制备络合染料(B-Fe^(2+))。采用红外光谱、紫外-可见分光光度法、表面能谱等对产物进行表征,证实了配位化合物的形成,黄芩苷与亚铁离子配位比为2∶1。将制备的B-Fe^(2+)用于蚕丝织物的印花,得到最佳汽蒸工艺为:汽蒸温度105℃、汽蒸时间20 min。在此条件下,B-Fe^(2+)对蚕丝织物印花具有较高的K/S值,各项色牢度均达到4级及以上,印花织物白底沾色较少。

Probiotic cocktails accelerate baicalin metabolism in the ileum to modulate intestinal health in broiler chickens

Background Baicalin and probiotic cocktails are promising feed additives with broad application prospects.While probiotic cocktails are known to enhance intestinal health,the potential synergistic impact of combining baicalin with probiotic cocktails on the gut health of broiler chickens remains largely unexplored.Therefore,this study aims to investigate the influence of the combined administration of baicalin and probiotic cocktails on the composition of ileal and cecal microbiota in broiler chickens to elucidate the underlying mechanisms responsible for the healthpromoting effects.Results A total of 3201-day-old male Arbor Acres broilers were divided into 4 groups,each with 8 replicates of 10 chicks per replicate.Over a period of 42 d,the birds were fed a basal diet or the same diet supplemented with 37.5 g/t baicalin(BC),1,000 g/t probiotic cocktails(PC),or a combination of both BC(37.5 g/t)and PC(1,000 g/t).The results demonstrated that BC+PC exhibited positive synergistic effects,enhancing intestinal morphology,immune function,and barrier function.This was evidenced by increased VH/CD ratio,sIgA levels,and upregulated expression of occludin and claudin-1(P<0.05).16S rRNA analysis indicated that PC potentiated the effects of BC,particularly in the ileum,where BC+PC significantly increased theα-diversity of the ileal microbiota,altered itsβ-diversity,and increased the relative abundance of Flavonifractor(P<0.05),a flavonoid-metabolizing bacterium.Furthermore,Flavonifractor positively correlated with chicken ileum crypt depth(P<0.05).While BC+PC had a limited effect on cecal microbiota structure,the PC group had a very similar microbial composition to BC+PC,suggesting that the effect of PC at the distal end of the gut overshadowed those of BC.Conclusions We demonstrated the synergistic enhancement of gut health regulation in broiler chickens by combining baicalin and probiotic cocktails.Probiotic cocktails enhanced the effects of baicalin and accelerated its metabolism in the ileum,thereby influencing the ileal microbiota structure.This study elucidates the interaction mechanism between probiotic cocktails and plant extract additives within the host microbiota.These findings provide compelling evidence for the future development of feed additive combinations.

Pharmacokinetic Comparison and Bioequivalence Evaluation of Two 20-mg Vonoprazan Fumarate Tablets in Bangladeshi Healthy Male Subjects

Background: Vonoprazan fumarate, a novel potassium-competitive acid blocker, outperforms traditional proton pump inhibitors in acid suppression and can be effectively combined with antibiotics to eradicate Helicobacter pylori. Objective: The study aimed to determine if two Vonoprazan formulations—Vonoprazan Fumarate 20 mg Tablet of Beximco Pharmaceuticals Limited, Bangladesh (test product) and Takecab 20 mg Tablet of Takeda Pharmaceutical Company Limited, Japan (reference product)—met FDA’s bioequivalence requirements by comparing their pharmacokinetic characteristics in healthy Bangladeshi adults. Methods: This was a single-center, randomized, open-label, two-period, two-sequence, laboratory-blind, double-crossover experiment. After 10 hours of fasting, 18 subjects were randomly assigned to receive a single oral dose of either formulation. During each treatment period, blood samples were collected at specific times (pre-dose and up to 48 hours post-dose) to measure plasma Vonoprazan levels using liquid chromatography-tandem mass spectrometry. A non-compartmental model was used to calculate pharmacokinetic parameters using the plasma drug concentration-time profile. A statistical comparison of the pharmacokinetic parameters of the two formulations of the test and reference product was conducted using SAS® statistical software to assess the bioequivalence. Primary pharmacokinetic parameters (Cmax, AUC0-t, and AUC0-∞) and secondary parameters (Tmax, T1/2, Kel, and AUC extrapolation) were calculated for both drug formulations. If the confidence intervals for the natural log-transformed Cmax, AUC0-t, and AUC0-∞ values fell between 80% and 125%, the drug products would be considered bioequivalent. Result: The geometric mean ratio of Vonoprazan between the test and reference groups was found to be 109.04% (99.47% - 119.53%), 101.37% (95.58% - 107.50%), and 101.24% (95.43% - 107.41%), with 90% confidence intervals (CIs) for the Cmax, AUC0–t, and AUC0–∞, and these outcomes met the regulatory requirements for assuming bioequivalence. Conclusion: The results demonstrated that the generic formulation of Vonoprazan 20 mg Tablet of Beximco Pharmaceuticals Limited is bioequivalent to the reference product.

Pretreatment and analysis techniques development of TKIs in biological samples for pharmacokinetic studies and therapeutic drug monitoring

Tyrosine kinase inhibitors(TKIs)have emerged as the first-line small molecule drugs in many cancer therapies,exerting their effects by impeding aberrant cell growth and proliferation through the modulation of tyrosine kinase-mediated signaling pathways.However,there exists a substantial inter-individual variability in the concentrations of certain TKIs and their metabolites,which may render patients with compromised immune function susceptible to diverse infections despite receiving theoretically efficacious anticancer treatments,alongside other potential side effects or adverse reactions.Therefore,an urgent need exists for an up-to-date review concerning the biological matrices relevant to bioanalysis and the sampling methods,clinical pharmacokinetics,and therapeutic drug monitoring of different TKIs.This paper provides a comprehensive overview of the advancements in pretreatment methods,such as protein precipitation(PPT),liquid-liquid extraction(LLE),solid-phase extraction(SPE),micro-SPE(μ-SPE),magnetic SPE(MSPE),and vortex-assisted dispersive SPE(VA-DSPE)achieved since 2017.It also highlights the latest analysis techniques such as newly developed high performance liquid chromatography(HPLC)and high-resolution mass spectrometry(HRMS)methods,capillary electrophoresis(CE),gas chromatography(GC),supercritical fluid chromatography(SFC)procedures,surface plasmon resonance(SPR)assays as well as novel nanoprobes-based biosensing techniques.In addition,a comparison is made between the advantages and disadvantages of different approaches while presenting critical challenges and prospects in pharmacokinetic studies and therapeutic drug monitoring.

Pharmacokinetic Characterization of Xylazine in Goats with Simultaneous Anesthesia Studies

The aim was to study the pharmacokinetics of xylazine as a stable anesthetic in goats.In this study,goats were injected with xylazine at the rate of 0.3 mL·kg-1 intramusculally,and blood samples were collected at 1,3,5,10,20,30,45,60,90,120,180,and 240 min after administration,respectively.Xylazine was extracted by liquid-liquid extraction and separation method,and blood concentration was determined by high performance liquid chromatography(HPLC).The pharmacokinetic characteristics of xylazine in healthy goats were analyzed by pharmacokinetic software.The results showed that the chromatographic peak time of xylazine chromatography was 9-11 min.The specificity of the method was good.The linear correlation coefficient R2 of the standard curve was 0.9982 when the concentration of xylazine was in the range of 10-1×1000 ng.The pharmacokinetic model of xylazine in goats was a one-chamber model with first-order rate absorption,distribution half-life t1/2Ka was(0.49±0.041)min,elimination half-life t1/2Ke was(23.3±2.5)min,and the peak time(Tp)of the highest concentration was(2.8±0.2)min.The total drug clearance CL/F was(0.00016±0.000016)mg·kg-1·min-1(ng·mL-1),and the minimum effective blood concentration was 56.6 ng·mL-1,which was consistent with the clinical anesthetic effect.The results showed that xylazine had the characteristics of rapid absorption,wide distribution,short peak time,slow clearance rate,and long anesthetic time in goats,which could be used as the basic drug for the development of goat complex anesthetic preparation.

Enhancement in Bioavailability of CurCousin®, A Minor Metabolite from Curcuma longa by Addition of BioPerine® —A Pharmacokinetic Study

In recent years, metabolic syndrome has been a growing health concern across the world. The role of nutraceuticals and functional foods in this area has a significant place due to the adverse effects of contemporary modes of treatment. CurCousin® is a nutritional ingredient containing bioactive Calebin A, (analog of Curcumin) with self-affirmed GRAS status. CurCousin® has been a clinically studied dietary supplement ingredient with a positive impact on body weight, lipid levels and metabolic health. Bioenhancers play an important role in increasing the bioavailability of the active in turn enhancing efficacy as well as reducing the dosage required to achieve the therapeutic effect. This study investigated the possible pharmacokinetic interaction between CurCousin® at two different doses (2.25 and 4.5 mg/kg) in the presence and absence of BioPerine® (0.27 mg/kg), a natural bioenhancer in Sprague-Dawley rats. The results revealed that the addition of BioPerine® into CurCousin® (2.25 mg/kg) half the dose when administered enhances the bioavailability and was equipotent to CurCousin® (4.5 mg/kg) double the dose without BioPerine®. Thus, leading to future clinical studies to evaluate its improved pharmacological efficacy as well as reduced therapeutic dosage.

Attenuation of the Activation of NLRP3 Inflammasome in Fibroblast Like Synoviocytes of Rheumatoid Arthritis by Baicalin through Regulating the Let-7i-3p/PI3K/Akt/NF-κB Signaling Axis

[Objectives]To study the effect and mechanism of baicalin on the activation of NLRP3 inflammasome in human fibroblast like synoviocytes of rheumatoid arthritis(HFLS-RA).[Methods]To confirm that baicalin alleviated the activation of NLRP3 inflammasome in HFLS-RA,the expression of NLRP3 before and after baicalin treatment was observed by immunofluorescence.Western blot was used to detect the protein expression of p-PI3K,p-Akt,NF-κB p65,NLRP3,ASC and caspase-1 after baicalin treatment for 48 h,and the contents of IL-1 and IL-18 in the supernatents were detected by ELISA.In order to explore the mechanism of baicalin alleviating the activation of NLRP3 inflammasome,the corresponding relationship between let-7i-3p and PIK3CA was verified by double luciferin and Westen blot analysis.The expression of let-7i-3p and PI3K before and after baicalin intervention was detected by RT-qPCR.let-7i-3p interference was used to verify whether baicalin mitigated the activation of enhanced NLRP3 inflammasome.[Results]Baicalin(50 and 100 mg/L)significantly reduced the activation of NLRP3 inflammasome,inhibited the protein expressions of p-PI3K,p-Akt,NF-κB p65,NLRP3,ASC and caspase-1,and the secretion of IL-1 and IL-18.let-7i-3p and PIK3CA had a targeted correspondence,and baicalin up-regulated the expression of let-7i-3p and down-regulated the expression of PIK3CA.Baicalin attenuated the activation of NLRP3 inflammasome enhanced by let-7i-3p interference.[Conclusions]Baicalin can up-regulate let-7i-3p expression,inhibit PI3K/Akt/NF-κB signal transduction,and thus reduce the activation of NLRP3 inflammasome in HFLS-RA.

Pharmacokinetics of Scutellarin in Dogs

Aim To establish an RP-HPLC method for the determination of scutellarin in plasma and study its pharmacokinetics in dogs. Methods Scutellarin was given to dogs by intravenous injection and determined by RP-HPLC, the mean plasma concentration-time curve was plotted and pharmacokinetic parameters were calculated by program 3p87. Resu;ts The concentration-time curve of scutellarin could be fitted to three-compartment model with T1/2 pi, T1/2 α and T1/2 β being 1.05 ± 0.80 min, 6.99 + 2.76 min and 51.61 + 28.78 min, respectively, Vc being 880.1 + 508.3 mL, CL being 189.6 + 53.8 mL@ min- 1, and AUC0-90 and AUC0-∞ being 574.43 + 133.95 μg@ min@ mL - 1 and 599.34 ± 132.00μg@ min@mL- 1, respectively. Conclusion The fact that the concentrations of scutellarin in plasma declined rapidly after the medication suggested that the T1/2 of scutellarin should be taken into account in drug administration and preparation development.

Determination of Loratadine in Human Plasma by High Performance Liquid Chromatography-Electrospray Mass Spectrometry and Studies on Its Pharmacokinetics and Relative Bioavailability

A new HPLC MS method to determine loratadine in human plasma was established. The method involved extracting drug with organic solvent under basic conditions. The samples were seperated by ODS column and determined by mass detector. The calibration curve of loratadine was linear within the range of 0.4～100 ng·mL -1 with r=0.9995 . The recovery of this method was within 95%～104%, within day and between day RSD were less than 12%. To study the pharmacokinetics and relative bioavailability of loratadine tablets, two formulations of loratadine tablets were given to 18 healthy male volunteers according to a randomized 2 way cross over design. The C max , AUC 0 t and T max values of the two formulations were 51.89±20.18 ng·mL -1 and 52.48±22.35 ng·mL -1 ; 140.75±88.42 ng·h·mL -1 and 147.24±92.33 ng·h·mL -1 ; 0.81±0.35 h and 0.81±0.27 h respectively. Results from statistic analysis showed that there were no significant difference between the C max , AUC 0-t and T max values of the two formulations. The relative bioavailability of tablets I with respect to tablets II was 97%±13% from the AUC 0 t measurement. Bioequivalance was observed between the two tablets.

Determination of Plasma Concentration of Cinnamic Acid by High-Performance Liquid Chromatography and Its Pharmacokinetics in Rats after Oral Administration of Zi-Shen Pill

Aim To develop a simple and sensitive high-performance liquid chromatographicmethod for determination of plasma concentration of cinnamic acid and pharmacokinetic study in ratsafter a single oral dose of traditional Chinese medicinal preparation Zi-Shen pill. Method Plasmasamples were acidified with hydrochloric acid and extracted with ethyl acetate . Cinnamic acid wasdetermined by HPLC using a G_(18) column. A mobile phase ofmethanbl-acetonitrile-water-triethyl-amine (7:22:73 = 0.2, V/V), with the pH adjusted to 4.0 withphosphoric acid, and with a UV detector set at 340 nm. Results The standard curve was linear overthe range of 1.92- 192.0 μg·mL^(-1). The LLOQ was 1.92 μg·mL^(-1) . The RSDs of within-day andbetween-day precision were < 8%. The mean recovery was 82.0% . Conclusion After validation, themethpd has been used to investigate the pharmacokinetic profiles of the traditional Chinesemedicinal preparation Zi-Shen pill.