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 ki...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.展开更多
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(CI...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).展开更多
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”(...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.展开更多
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 we...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.展开更多
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 (DF...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.展开更多
AIM To propose a hypothesis defining theabsorption,distribution,metabolism andelimination of traditional Chinese recipe（TCR）-component in blood of healthy subjects andpatients,and estimate its correctness.METHODS Th...AIM To propose a hypothesis defining theabsorption,distribution,metabolism andelimination of traditional Chinese recipe（TCR）-component in blood of healthy subjects andpatients,and estimate its correctness.METHODS The pharmacokinetics（PK）of samedose of drug was studied in the animal model oftraditional Chinese syndrome（S）and healthyanimals.The classification,terminology,concept and significance of the hypothesis wereset forth with evidence provided in the presentstudy.The hypotheses consisted of traditionalChinese syndrome PK（S-PK）and traditionalChinese recipe PK（R-PK）.Firstly,the observedtetramethylpyrazine（TMP）PK in healthy,chronically reserpinized rats（rat model ofspleen deficiency syndrome,RMSDS）andRMSDS treated with Sijunzi decoction（SJZD）forconfirmation were used to verify S-PK; secondly,the ferulic acid（FA）PK in healthy andhigh molecular weight dextran（HMWD）-inducedrabbit model with blood stasis syndrome（RDBSS）was also used to verify S-PK;andlastly,TMP PK parameters in serum of healthyrats after orally taken Ligusticum wallichii（LW）,LW and Salvia miltiorrhiza（LW&SM）decoctions were compared to verify R-PK.RESULTS The apparent first-order absorption[Ka,（13.61±2.56）h<sup>-1</sup>,area under the blooddrug concentration-time curve[AUC,（24.88±9.76）μg.h<sup>-1</sup>mL<sup>-1</sup>],maximum drug concentration[C<sub>max</sub>,（4.82±1.23）μg·mL<sup>-1</sup>]of serum TMP inRMSDS were increased markedly（P【0.05）compared with those[Ka=（5.41±1.91）h<sup>-1</sup>,AUC=（5.20±2.57）μg·h<sup>-1</sup>·mL<sup>-1</sup>,C<sub>max</sub>=（2.33±1.77）μg·mL<sup>-1</sup>]of healthy rats（HR）.Theapparent first-order rate constant for α and βdistribution phase[α=（0.38±0.09）h<sup>-1</sup>,β=（0.06±0.03）h<sup>-1</sup>,the apparent first-orderintercompartmental transfer rate constants[K<sub>10</sub>=（0.24±0.07）h<sup>-1</sup>,K<sub>12</sub>=（0.11±0.02）h<sup>-1</sup>,K<sub>21</sub>=（0.11±0.02）h<sup>-1</sup>]of serum TMP in RMSDS weredecreased significantly（P【0.01）comparedwith those[K<sub>10</sub>=（0.88±0.20）h<sup>-1</sup>,K<sub>12</sub>=（1.45±0.47）h<sup>-1</sup>,K<sub>21</sub>=（0.72±0.22）h<sup>-1</sup>]of HR.However,no apparent differences occurredbetween HR and RMSDS treated with SJZD.Theserum FA concentration and its AUC[（5.6690±2.3541）μg·h<sup>-1</sup>·mL<sup>-1</sup>] in RMBSS were also higherthan those[AUC=（2.7566±0.8232）μg·h<sup>-1</sup>·mL<sup>-1</sup>]of healthy rabbits（P【0.05）.The Ka（11.51±2.82）h<sup>-1</sup>,AUC（0.84±0.17）μg·h<sup>-1</sup>·mL<sup>-1</sup>of LW & SM-derived TMP in serum weremuch lower（P【0.05）than those[Ka=（19.58±4.14）h<sup>-1</sup>,AUC=（1.27±0.26）μg·h<sup>-1</sup>·mL<sup>-1</sup>]ofLW-derived TMP in serum after oral decoctions.CONCLUSION The SDS and blood stasissyndrome state could affect significantly thepharmacokinetic parameters of drugs and theabnormal SDS pharmacokinetic parameters couldbe normalized by SJZD.The combination ofChinese medicine in TCR could reciprocallyaffect the pharmacokinetic parameters of othercomponents absorbed into the systemiccirculation.These results support the S-and R-PK hypothesis.展开更多
AIM To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction(DCQD) in the liver of rats with severe acute pancreatitis(SAP) based on an herbal recipe tissue pharmacology hypothesis.METHODS Healthy...AIM To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction(DCQD) in the liver of rats with severe acute pancreatitis(SAP) based on an herbal recipe tissue pharmacology hypothesis.METHODS Healthy male Sprague-Dawley rats were randomly divided into a sham operation group(SOG); a model group(MG); and low-, median- and high-dose treatment groups(LDG, MDG, and HDG, respectively). Different dosages(6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloeemodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase(ALT) and aspartate transaminase(AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated.RESULTS The major components of DCQD were detected in the liver, and their concentrations increased dosedependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-α and interleukin(IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG(P < 0.05). DCQD could reduce the pathological scores in the pancreas and liver of the rats with SAP, especially in the HDG. Compared to the SOG, the ALT and AST levels in serum were higher in the MG(P < 0.05), while there was no statistical difference in the MG and HDG.CONCLUSION DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.展开更多
Ziziphi Spinosae Semen(ZSS),a traditional Chinese medicine,is used in clinics for the treatment of insomnia in China and other Asian countries.Herein,we described for the first time a comparative pharmacokinetics stud...Ziziphi Spinosae Semen(ZSS),a traditional Chinese medicine,is used in clinics for the treatment of insomnia in China and other Asian countries.Herein,we described for the first time a comparative pharmacokinetics study of the six major compounds of ZSS in normal control(NC)and para-chlorophenylalanine(PCPA)-induced insomnia model(IM)rats that were orally administered the aqueous extract of ZSS.An ultra-high-performance liquid chromatography coupled with quadrupole orbitrap mass(UHPLC-Q-Orbitrap-MS)method was developed and validated for the simultaneous determination of coclaurine,magnoflorine,spinosin,6000-feruloylspinosin,jujuboside A(JuA),and jujuboside B(JuB)in ZSS in rat plasma.The established approach was successfully applied to a comparative pharmacokinetic study.The systemic exposures of spinosin and 6000-feruloylspinosin were decreased in the IM group compared to the NC group,while plasma clearance(CL)was significantly increased.The Tmax values of JuA and JuB in IM rats were significantly lower than those in NC rats.The T1/2 of JuA in the IM group was significantly accelerated.The pharmacokinetic parameters of coclaurine and magnoflorine were not evidently affected between the two groups.These results indicate that the pathological state of insomnia altered the plasma pharmacokinetics of spinosin,6000-feruloylspinosin,JuA,and JuB in the ZSS aqueous extract,providing an experimental basis for the role of ZSS in insomnia treatment.The comparative pharmacokinetics-based UHPLC-Q-Orbitrap-MS using full-scan mode can therefore provide a reliable and suitable means for the screening of potentially effective substances applied as quality markers of ZSS.展开更多
AIM To explore the pharmacokinetics and pharmacodynamics of Shengjiang decoction(SJD) in rats with acute pancreatitis(AP) for protecting against multiple organ injury.METHODS An AP model was established by retrograde ...AIM To explore the pharmacokinetics and pharmacodynamics of Shengjiang decoction(SJD) in rats with acute pancreatitis(AP) for protecting against multiple organ injury.METHODS An AP model was established by retrograde perfusion of 3.5% sodium taurocholate into the biliopancreatic duct, and a control group(CG) received 0.9% sodium chloride instead. Twelve male Sprague-Dawley rats were randomly divided into a CG treated with SJD(CG + SJD) and a model group treated with SJD(MG + SJD), both of which were orally administered with SJD(5 g/kg) 2 h after surgery. Blood samples were collected via the tail vein at 10, 20, and 40 min and 1, 2, 3, 4, 6, 8, and 12 h after a single dose of SJD to detect its main components using high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were compared. In the pharmacodynamic experiment, 18 male SpragueDawley rats were randomly divided into a CG, an AP model group(MG), and an SJD treated AP group(SJDG). Serum amylase, lipase, and inflammatory cytokines were measured, and heart, lung, liver, spleen, pancreas, kidney, and intestine tissues were collected for pathological examination.RESULTS The MG + SJD displayed significantly shorter mean residence time(MRT) and higher clearance(CL) for emodin and aloe-emodin; significantly shorter time of maximum concentration and T1/2 and a lower area under curve(AUC) for aloe-emodin; a significantly higher AUC and lower CL for rhein; and longer MRT and lower CL for chrysophanol than the CG + SJD. In the pharmacodynamic experiment, the amylase, interleukin(IL)-6, IL-10, and tumor necrosis factor(TNF)-α levels in the MG were higher than those in the CG(P < 0.05). After the herbal decoction treatment, the SJDG had higher IL-10 and lower TNF-α levels than the MG(P < 0.05). The MG had the highest pathological scores, and the pathological scores of the lung, pancreas, kidney, and intestine in the SJDG were significantly lower than those in the MG(P < 0.05).CONCLUSION AP may have varying effects on the pharmacokinetics of the major SJD components in rats. SJD might alleviate pathological injuries of the lung, pancreas, kidney, and intestine in rats with AP via regulating pro-and antiinflammatory responses, which might guide the clinical application of SJD for AP treatment.展开更多
Objective:This study aimed to develop a new polyethylene glycol(PEG)ylatedβ-elemene liposome(PEG-Lipo-β-E)and evaluate its characterization,pharmacokinetics,antitumor effects and safety in vitro and in vivo.Methods:...Objective:This study aimed to develop a new polyethylene glycol(PEG)ylatedβ-elemene liposome(PEG-Lipo-β-E)and evaluate its characterization,pharmacokinetics,antitumor effects and safety in vitro and in vivo.Methods:The liposomes were prepared by ethanol injection and high-pressure micro-jet homogenization.Characterization of the liposomes was conducted,and drug content,entrapment efficiency(EE),in vitro release and stability were studied by ultra-fast liquid chromatography(UFLC)and a liquid surface method.Blood was drawn from rats to establish the pharmacokinetic parameters.The anticancer effect was evaluated in a KU-19-19 bladder cancer xenograft model.Histological analyses were performed to evaluate safety.Results:The PEG-Lipo-β-E showed good stability and was characterized as 83.31±0.181 nm in size,0.279±0.004 in polydispersity index(PDI),-21.4±1.06 mV in zeta potential,6.65±0.02 in pH,5.024±0.107 mg/mL inβ-elemene(β-E)content,and 95.53±1.712%in average EE.The Fourier transform infrared spectroscopy(FTIR)and differential scanning calorimetry(DSC)indicated the formation of PEG-Lipo-β-E.Compared to elemene injection,PEG-Lipo-β-E demonstrated a 1.75-fold decrease in clearance,a 1.62-fold increase in half-life,and a 1.76-fold increase in area under the concentration-time curves(AUCs)from 0 hour to 1.5 hours(P<0.05).PEG-Lipo-β-E also showed an enhanced anticancer effect in vivo.Histological analyses showed that there was no evidence of toxicity to the heart,kidney,liver,lung or spleen.Conclusions:The present study demonstrates PEG-Lipo-β-E as a new formulation with ease of preparation,high EE,good stability,improved bioavailability and antitumor effects.展开更多
Objective: This study aimed to compare the pharmacokinetic, pharmacodynamic and safety profiles of HLX01(a rituximab biosimilar) and reference rituximab sourced from China(Mab Thera?;rituximab-CN).Methods: Here we rep...Objective: This study aimed to compare the pharmacokinetic, pharmacodynamic and safety profiles of HLX01(a rituximab biosimilar) and reference rituximab sourced from China(Mab Thera?;rituximab-CN).Methods: Here we report the results of two phase 1 studies. In the phase 1 a, open-label, dose-escalation study(NCT03218072, CTR20140400), eligible patients received 250, 375 and 500 mg/m^(2) HLX01 sequentially at 7-day intervals, after confirming no dose-limiting toxicity(DLT). In the phase 1 b, double-blind study(NCT02584920,CTR20140764), eligible patients were given a single dose of 375 mg/m^(2) HLX01 or rituximab-CN. The primary endpoints included safety and tolerability parameters for the phase 1 a and the area under the plasma concentrationtime curve from time zero to day 91(AUC0-91 d) for the phase 1 b study. Equivalence was concluded if 90%confidence interval(90% CI) for the geometric least squares mean ratio(GLSMR) fell in the pre-specified equivalence criteria(80%-125%).Results: Between June 20, 2014 and January 5, 2015, 12 patients were enrolled in the phase 1 a study. The pharmacokinetics of HLX01 showed dose proportionality and accumulation to steady state. HLX01 was well tolerated, with no serious adverse events(AEs), discontinuations or DLTs. Between November 8, 2014 and August13, 2015, 87 eligible patients were enrolled in the phase 1 b study, including 43 who received HLX01 and 44 who were treated with rituximab-CN. The equivalence endpoint was met with GLSMR for AUC0-91 d being 89.6%(90% CI: 80.4%-99.8%). AEs, anti-drug antibodies, and CD19+ and CD20+ B lymphocyte counts were similar between the HLX01 and rituximab-CN treatment groups.Conclusions: Treatment with HLX01 was safe and well tolerated in Chinese patients with B-cell lymphoma.HLX01 and rituximab-CN have similar pharmacokinetic, pharmacodynamic and safety profiles.展开更多
Jervine,a novel steroidal alkaloid from Veratrum nigrum L.,exhibits both antitumor effect and potential toxicity.The aim of study was to characterize the pharmacokinetic behaviors and enterohepatic circulation of jerv...Jervine,a novel steroidal alkaloid from Veratrum nigrum L.,exhibits both antitumor effect and potential toxicity.The aim of study was to characterize the pharmacokinetic behaviors and enterohepatic circulation of jervine in rats.A rapid and simple ultra-high performance liquid chromatography-tandem mass spectrometric method was developed and validated for quantification of jervine and alpinetin (internal standard) in rat plasma.After extraction from rat plasma by a simple protein-precipitation method,the analyte was separated on a C18 column (2.1 mm×50 mm,1.7μm) using water with 0.1%formic acid and acetonitrile as the mobile phase delivered at a flow rate of 0.4mL/min.Jervine and alpinetin were determined in the positive mode with multiple reaction monitoring (MRM) of the ion transitions at m/z426.3→108.8 and m/z 271.0 166.9,respectively.Molecular docking method was used to investigate the binding of jervine to p-glycoprotein and dehydroepiandrosterone sulfotransferase.The method was well validated within acceptance limits including specificity,matrix effect,recovery,precision,accuracy,and stability,and was successfully applied to the pharmacokinetic study of jervine after oral and intravenous administration to rats.Jervine presented a small volume of distribution,fast absorption,high oral bioavailability,and enterohepatic circulation.The enterohepatic circulation was first observed in veratrum alkaloids,and was further investigated by molecular docking studies,which was related to the binding of jervine to p-glycoprotein and dehydroepiandrosterone sulfotransferase.The pharmacokinetic properties and enterohepatic circulation of jervine in rats provided a significant basis for the drug-drug interaction and toxicity study in the future.展开更多
Timataxel(13-(N-Boc-3-i-butylisoserinoyl-4,10-β-diacetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,13-α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene)), used to be called TM-2, is a novel semi-synthetic promising candidate f...Timataxel(13-(N-Boc-3-i-butylisoserinoyl-4,10-β-diacetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,13-α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene)), used to be called TM-2, is a novel semi-synthetic promising candidate for cancer treatment. However the preformulation study showed that TM-2 was insoluble and chemically instable in water, which would limit its application. This study aimed at the preparation of Timataxel lipid microspheres(TM-2 LMs)and investigated the difference between TM-2 LMs and TM-2 solution in pharmacokinetics. In this work, the final formulation was as follows: 0.10%(w/v) TM-2;10.00%(w/v) oil phase(long chain triglyceride:media chain triglyceride = 2.50%:7.50%);1.40%(w/v) phospholipid;0.02%(w/v) NaH2 PO4;2.25%(w/v) glycerin and water to a total volume of 100 ml.The particle size distribution, content and entrapment efficacy were 205.0 ± 43.3 nm, 101.00% and 99.12%, respectively. TM-2 LMs were stable during storage at 25 °C for 3 months, even under the condition of 60 °C and 4500 lx for 10 d. Phosphatidylethanolamine(PE) in phospholipid may contribute to the stability of TM-2 LMs. The pharmacokinetic parameters for TM-2 LMs were as follows: AUC(0-∞) 3663.71 μg/l h and the clearance 2.26 l/h/kg. As for solution, these parameters were 1712.52 μg/l h and 4.77 l/h/kg, respectively. The t1/2 of TM-2 LMs was similar to TM-2 solution. The pharmacokinetic results indicated that the AUC of TM-2 LMs was larger, the clearance was smaller than that of TM-2 solution. In a word, lipid microspheres were a promising drug delivery system for TM-2.展开更多
OBJECTIVE To determine the characterization,anti-tumor efficacy and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity.METHODS Bufalin-loaded PEGylated liposomes and bufalin-loaded lip...OBJECTIVE To determine the characterization,anti-tumor efficacy and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity.METHODS Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high pressure homogenization method.The particle size and zeta potential of the liposomes were determined by dynamic light scattering technique.The direct imaging of morphology of liposomes was charactered by transmission electron microscope.The content of bufalin in liposomes was analysed by HPLC method.The entrapment efficiency and the particle size was applied to assess the stability profile,after storage at 4℃ on day 0,7,15,30 and 90.The in-vitro release behaviours of bufalin from liposomes were conducted using dialysis bag technique at 37℃.In-vitro cytotoxicity studies were carried out using MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]assay on several kinds of tumor cel lines including SW620,PC-3,MDA-MB-231,A549,U251,U87 and HepG2.In-vivo pharmacokinetic study of bufalin liposomes was evaluated by HPLC method.RESULTS Their mean particle sizes were 127.6 nm and 155.0 nm,mean zeta potentials were 2.24 m V and-18.5 m V,entrapment efficiencies were 76.31%and 78.40%,respectively.In-vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that of bufalin-loaded liposomes.The cytotoxicity of blank liposomes has been found within acceptable range,whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity.In-vivo pharmacokinetics indicated that bufalinloaded PEGylated liposomes could extend eliminate half-life time of bufalin in plasma in rats.CONCLUSION The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma.展开更多
A pH-responsive conjugate based 10-hydroxycamptothecin-thiosemicarbazide-polyethene glycol 2000 (10-HCPT-hydro-PEG) nano-micelles were prepared in our previous study. In the present study, ultra-performance liquid chr...A pH-responsive conjugate based 10-hydroxycamptothecin-thiosemicarbazide-polyethene glycol 2000 (10-HCPT-hydro-PEG) nano-micelles were prepared in our previous study. In the present study, ultra-performance liquid chromatography (UPLC-MS) method is developed to investigate its pharmacokinetics and biodistribution in tumor bearing mice. The results demonstrated that the conjugate circulated for a much longer time in the blood circulation system than commercial 10-HCPT injection, and bioavailability was significantly improved compared with 10-HCPT. In vivo biodistribution study showed that the conjugate could enhance the targeting and residence time in tumor site.展开更多
One purpose of this study was to develop a paliperidone(PAL)tri-layer ascending release pushepull osmotic pump(TA-PPOP)tablet which could meet the needs of clinical applications.And another purpose was to investigate ...One purpose of this study was to develop a paliperidone(PAL)tri-layer ascending release pushepull osmotic pump(TA-PPOP)tablet which could meet the needs of clinical applications.And another purpose was to investigate whether different coating materials influenced in vivo performance of TA-PPOP.The ascending release mechanism of this trilayer delivery system on theory was elaborated.TA-PPOP was prepared by means of coating with cellulose acetate(CA)or ethyl cellulose(EC).Several important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated.The optimization of formulation and process was conducted by comparing different in vitro release behaviors of PAL.In vitro dissolution studies indicated that both the two formulations of different coating materials were able to deliver PAL at an ascending release rate during the whole 24 h test.The in vivo pharmacokinetics study showed that both self-made PPOP tablets with different coating had a good in vitro-in vivo correlation(IVIVC)and were bioequivalent with the brand product,which demonstrated no significant influence of the coating materials on the in vivo release acceleration of TA-PPOP.展开更多
The aim of the present study was to develop a novel long-acting Poly(lactic-co-glycolic acid)(PLGA)-based microspheres formulation of Bisdemethoxycurcum(BDMC) by emulsionsolvent evaporation method. Meanwhile, the effe...The aim of the present study was to develop a novel long-acting Poly(lactic-co-glycolic acid)(PLGA)-based microspheres formulation of Bisdemethoxycurcum(BDMC) by emulsionsolvent evaporation method. Meanwhile, the effects of the volume ratio of the dispersed phase and continuous phase, the concentration of PLGA and PVA, the theoretical drug loading and stirring speed were investigated. The mean diameter of the microspheres was 8.5 μm and the size distribution was narrow. The encapsulation efficiency(EE) and drug loading efficiency(DLE) of BDME loaded PLGA microspheres(BDMC-PLGA-MS) was 94.18% and 8.14%,respectively. In an in vitro study of drug release, it can be concluded that the BDMC-PLGAMS exhibited sustained and long-term release properties for 96 h. Stability studies suggested that the microspheres we prepared had a very good stability. Furthermore, the results of an in vivo study indicated that the BDMC-PLGA-MS had sustained release effect and was mainly distributed in the lung tissue, and less distribution in other tissues, which indicated that microspheres could be an effective parenteral carrier for the delivery of BDMC in lung cancer treatment.展开更多
Significant progress has been made in understanding pharmacokinetics (PK),pharmacodynamics (PD),as well as toxicity profiles of therapeutic proteins in animals and humans,which have been in commercial development for ...Significant progress has been made in understanding pharmacokinetics (PK),pharmacodynamics (PD),as well as toxicity profiles of therapeutic proteins in animals and humans,which have been in commercial development for more than three decades.However,in the PK arena,many fundamental questions remain to be resolved.Investigative and bioanalytical tools need to be established to improve the translation of PK data from animals to humans,and from in vitro assays to in vivo readouts,which would ultimately lead to a higher success rate in drug development.In toxicology,it is known,in general,what studies are needed to safely develop therapeutic proteins,and what studies do not provide relevant information.One of the major complicating factors in nonclinical and clinical programs for therapeutic proteins is the impact of immunogenicity.In this review,we will highlight the emerging science and technology,as well as the challenges around the pharmacokinetic-and safety-related issues in drug development of mAbs and other therapeutic proteins.展开更多
This work was done to investigate succinylated commercial whey protein isolate(S-WPI)as an oral sustained-release delivery carrier for puerarin 5(PR-5). The succinylation condi-tions were established for S-WPIs by opt...This work was done to investigate succinylated commercial whey protein isolate(S-WPI)as an oral sustained-release delivery carrier for puerarin 5(PR-5). The succinylation condi-tions were established for S-WPIs by optimization of single factor study and Box–Beehnkendesign. The effect of succinylation degree on S-WPIs solubility was evaluated. Physicochem-ical properties of S-WPIs dried by different three methods on their flow ability, particle size,morphology and in vitro release behavior were studied. After preparing PR-5 sustained re-lease protein tablets with S-WPIs as the carrier by direct powder compression method, thedrug release were studied in vitro and the oral pharmacokinetics and bioavailability wasevaluated using in vivo dog model. It was observed that concentration of substrate has asignificant effect on succinylation. Release behavior in vitro showed spry dried S-WPIs with100% succinylation rate and 30% drug loading would be applied to the preparation of PR-5 sustained-release protein tablets based on the swelling mechanism(protein loss). Comparedwith PR-5 conventional tablet with oral administration, T max value of PR-5 sustained-releaseprotein tablets was approximately 1.58 fold greater than those of the conventional tablets asfurther evidenced by the significantly prolonged MRT and T 1/2. The findings demonstratedthat spray-dried S-WPIs has potential as a promising functional excipient for the design of PR-5 oral sustained-release tablets which can fully improve sustained-release effect and oral bioavailability.展开更多
Adenosine triphosphate-binding cassette transporter breast cancer resistance protein(BCRP) exists highly in the apical membranes of epithelia, and is involved in drug availability. Ko143 is a typical inhibitor of BCRP...Adenosine triphosphate-binding cassette transporter breast cancer resistance protein(BCRP) exists highly in the apical membranes of epithelia, and is involved in drug availability. Ko143 is a typical inhibitor of BCRP in rodents. The synthetic antibacterial agent enrofloxacin(ENRO) is a fluoroquinolone employed as veterinary and aquatic medicine, and also a substrate for BCRP. BCRP gene highly expressed in the hepatopancreas and intestine of Exopalaemon carinicauda as was determined with real-time quantitative reverse transcription-polymerase chain reaction(RT-q PCR) method. The effects of Ko143 on the abundance of BCRP m RNA and ENRO pharmacokinetics in E. carinicauda were studied. The m RNA abundance of BCRP decreased significantly in hepatopancreas and intestine(P < 0.05) after Ko143 treatment. Co-administration of Ko143 significantly changed the pharmacokinetics of orally administered enrofloxacin, which was supported by higher distribution half-life(t_(1/2α)), elimination half-life(t_(1/2β)), area under the curve up to the last measurable concentration(AUC_(0-t)), peak concentration(C_(max)) and lower clearance(CL/F). These findings revealed that Ko143 downregulates BCRP expression in hepatopancreas and intestine, thus affects the pharmacokinetics of orally administered enrofloxacin in E. carinicauda. The drug-drug interaction can be caused by the change in BCRP activity if ENRO is used in combination with other drugs in shrimp.展开更多
基金Supported by the National Natural Science Foundation of China (Nos.42176137,81872906)the Nantong Science and Technology Project (No.MS12021037)+2 种基金the STS Program of Chinese Academy of Sciences (No.KFJ-STS-QYZD-195)the K.C.Wong Education FoundationCAS。
文摘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.
基金supported by the Central Public-Interest Scientific Institution Basal Research Fund,CAFS(No.2020TD71).
文摘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).
基金supported by Ningbo Natural Science Foundation(Grant No.:2022J229)Project of Ningbo Leading Medical&Health Discipline(Project No.:2022-S04)+1 种基金Opened-end Fund of Key Laboratory(Grant No.:KFJJ-202101)Graduate Student Scientific Research and Innovation Fund of Ningbo University(Grant No.:IF2022193)。
文摘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.
基金This study was supported by Key Research and Development Guidance Program of Heilongjiang Province(GZ20210125)。
文摘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.
文摘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.
基金National Natural Science Foundation of China,No.398709323967086539570870 and 39100139.
文摘AIM To propose a hypothesis defining theabsorption,distribution,metabolism andelimination of traditional Chinese recipe（TCR）-component in blood of healthy subjects andpatients,and estimate its correctness.METHODS The pharmacokinetics（PK）of samedose of drug was studied in the animal model oftraditional Chinese syndrome（S）and healthyanimals.The classification,terminology,concept and significance of the hypothesis wereset forth with evidence provided in the presentstudy.The hypotheses consisted of traditionalChinese syndrome PK（S-PK）and traditionalChinese recipe PK（R-PK）.Firstly,the observedtetramethylpyrazine（TMP）PK in healthy,chronically reserpinized rats（rat model ofspleen deficiency syndrome,RMSDS）andRMSDS treated with Sijunzi decoction（SJZD）forconfirmation were used to verify S-PK; secondly,the ferulic acid（FA）PK in healthy andhigh molecular weight dextran（HMWD）-inducedrabbit model with blood stasis syndrome（RDBSS）was also used to verify S-PK;andlastly,TMP PK parameters in serum of healthyrats after orally taken Ligusticum wallichii（LW）,LW and Salvia miltiorrhiza（LW&SM）decoctions were compared to verify R-PK.RESULTS The apparent first-order absorption[Ka,（13.61±2.56）h<sup>-1</sup>,area under the blooddrug concentration-time curve[AUC,（24.88±9.76）μg.h<sup>-1</sup>mL<sup>-1</sup>],maximum drug concentration[C<sub>max</sub>,（4.82±1.23）μg·mL<sup>-1</sup>]of serum TMP inRMSDS were increased markedly（P【0.05）compared with those[Ka=（5.41±1.91）h<sup>-1</sup>,AUC=（5.20±2.57）μg·h<sup>-1</sup>·mL<sup>-1</sup>,C<sub>max</sub>=（2.33±1.77）μg·mL<sup>-1</sup>]of healthy rats（HR）.Theapparent first-order rate constant for α and βdistribution phase[α=（0.38±0.09）h<sup>-1</sup>,β=（0.06±0.03）h<sup>-1</sup>,the apparent first-orderintercompartmental transfer rate constants[K<sub>10</sub>=（0.24±0.07）h<sup>-1</sup>,K<sub>12</sub>=（0.11±0.02）h<sup>-1</sup>,K<sub>21</sub>=（0.11±0.02）h<sup>-1</sup>]of serum TMP in RMSDS weredecreased significantly（P【0.01）comparedwith those[K<sub>10</sub>=（0.88±0.20）h<sup>-1</sup>,K<sub>12</sub>=（1.45±0.47）h<sup>-1</sup>,K<sub>21</sub>=（0.72±0.22）h<sup>-1</sup>]of HR.However,no apparent differences occurredbetween HR and RMSDS treated with SJZD.Theserum FA concentration and its AUC[（5.6690±2.3541）μg·h<sup>-1</sup>·mL<sup>-1</sup>] in RMBSS were also higherthan those[AUC=（2.7566±0.8232）μg·h<sup>-1</sup>·mL<sup>-1</sup>]of healthy rabbits（P【0.05）.The Ka（11.51±2.82）h<sup>-1</sup>,AUC（0.84±0.17）μg·h<sup>-1</sup>·mL<sup>-1</sup>of LW & SM-derived TMP in serum weremuch lower（P【0.05）than those[Ka=（19.58±4.14）h<sup>-1</sup>,AUC=（1.27±0.26）μg·h<sup>-1</sup>·mL<sup>-1</sup>]ofLW-derived TMP in serum after oral decoctions.CONCLUSION The SDS and blood stasissyndrome state could affect significantly thepharmacokinetic parameters of drugs and theabnormal SDS pharmacokinetic parameters couldbe normalized by SJZD.The combination ofChinese medicine in TCR could reciprocallyaffect the pharmacokinetic parameters of othercomponents absorbed into the systemiccirculation.These results support the S-and R-PK hypothesis.
基金Supported by National Natural Science Foundation of China,No.81374042,No.81370091 and No.81573857
文摘AIM To explore the pharmacokinetics and pharmacodynamics of Da-Cheng-Qi decoction(DCQD) in the liver of rats with severe acute pancreatitis(SAP) based on an herbal recipe tissue pharmacology hypothesis.METHODS Healthy male Sprague-Dawley rats were randomly divided into a sham operation group(SOG); a model group(MG); and low-, median- and high-dose treatment groups(LDG, MDG, and HDG, respectively). Different dosages(6, 12 and 24 g/kg for the LDG, MDG, and HDG, respectively) of DCQD were administered to the rats with SAP. The tissue concentrations of aloeemodin, rhein, emodin, chrysophanol, honokiol, rheo chrysophanol, magnolol, hesperidin, naringenin and naringin in the liver of the treated rats were detected by high-performance liquid chromatography tandem mass spectrometry. Alanine transaminase(ALT) and aspartate transaminase(AST) in serum, inflammatory mediators in the liver and pathological scores were evaluated.RESULTS The major components of DCQD were detected in the liver, and their concentrations increased dosedependently. The high dose of DCQD showed a maximal effect in ameliorating the pathological damages, decreasing the pro-inflammatory mediators tumor necrosis factor-α and interleukin(IL)-6 and increasing anti-inflammatory mediators IL-4 and IL-10 in the liver. The pathological scores in the pancreas for the MG were significantly higher than those for the SOG(P < 0.05). DCQD could reduce the pathological scores in the pancreas and liver of the rats with SAP, especially in the HDG. Compared to the SOG, the ALT and AST levels in serum were higher in the MG(P < 0.05), while there was no statistical difference in the MG and HDG.CONCLUSION DCQD could alleviate liver damage by altering the inflammatory response in rats with SAP based on the liver distribution of its components.
基金This work was supported by grants from the National Natural Science Foundation of China(No:81603289,81603251)Key Laboratory of Effective Substances Research and Utilization in TCM of Shanxi province(No:201605D111004)and Key Technology Research Zhen Dong Special Project from Shanxi Science and Technology Department(No:2016ZD0105).
文摘Ziziphi Spinosae Semen(ZSS),a traditional Chinese medicine,is used in clinics for the treatment of insomnia in China and other Asian countries.Herein,we described for the first time a comparative pharmacokinetics study of the six major compounds of ZSS in normal control(NC)and para-chlorophenylalanine(PCPA)-induced insomnia model(IM)rats that were orally administered the aqueous extract of ZSS.An ultra-high-performance liquid chromatography coupled with quadrupole orbitrap mass(UHPLC-Q-Orbitrap-MS)method was developed and validated for the simultaneous determination of coclaurine,magnoflorine,spinosin,6000-feruloylspinosin,jujuboside A(JuA),and jujuboside B(JuB)in ZSS in rat plasma.The established approach was successfully applied to a comparative pharmacokinetic study.The systemic exposures of spinosin and 6000-feruloylspinosin were decreased in the IM group compared to the NC group,while plasma clearance(CL)was significantly increased.The Tmax values of JuA and JuB in IM rats were significantly lower than those in NC rats.The T1/2 of JuA in the IM group was significantly accelerated.The pharmacokinetic parameters of coclaurine and magnoflorine were not evidently affected between the two groups.These results indicate that the pathological state of insomnia altered the plasma pharmacokinetics of spinosin,6000-feruloylspinosin,JuA,and JuB in the ZSS aqueous extract,providing an experimental basis for the role of ZSS in insomnia treatment.The comparative pharmacokinetics-based UHPLC-Q-Orbitrap-MS using full-scan mode can therefore provide a reliable and suitable means for the screening of potentially effective substances applied as quality markers of ZSS.
基金Supported by the National Natural Science Foundation of China,No.81603519,No.81573857,and No.81374042
文摘AIM To explore the pharmacokinetics and pharmacodynamics of Shengjiang decoction(SJD) in rats with acute pancreatitis(AP) for protecting against multiple organ injury.METHODS An AP model was established by retrograde perfusion of 3.5% sodium taurocholate into the biliopancreatic duct, and a control group(CG) received 0.9% sodium chloride instead. Twelve male Sprague-Dawley rats were randomly divided into a CG treated with SJD(CG + SJD) and a model group treated with SJD(MG + SJD), both of which were orally administered with SJD(5 g/kg) 2 h after surgery. Blood samples were collected via the tail vein at 10, 20, and 40 min and 1, 2, 3, 4, 6, 8, and 12 h after a single dose of SJD to detect its main components using high-performance liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters were compared. In the pharmacodynamic experiment, 18 male SpragueDawley rats were randomly divided into a CG, an AP model group(MG), and an SJD treated AP group(SJDG). Serum amylase, lipase, and inflammatory cytokines were measured, and heart, lung, liver, spleen, pancreas, kidney, and intestine tissues were collected for pathological examination.RESULTS The MG + SJD displayed significantly shorter mean residence time(MRT) and higher clearance(CL) for emodin and aloe-emodin; significantly shorter time of maximum concentration and T1/2 and a lower area under curve(AUC) for aloe-emodin; a significantly higher AUC and lower CL for rhein; and longer MRT and lower CL for chrysophanol than the CG + SJD. In the pharmacodynamic experiment, the amylase, interleukin(IL)-6, IL-10, and tumor necrosis factor(TNF)-α levels in the MG were higher than those in the CG(P < 0.05). After the herbal decoction treatment, the SJDG had higher IL-10 and lower TNF-α levels than the MG(P < 0.05). The MG had the highest pathological scores, and the pathological scores of the lung, pancreas, kidney, and intestine in the SJDG were significantly lower than those in the MG(P < 0.05).CONCLUSION AP may have varying effects on the pharmacokinetics of the major SJD components in rats. SJD might alleviate pathological injuries of the lung, pancreas, kidney, and intestine in rats with AP via regulating pro-and antiinflammatory responses, which might guide the clinical application of SJD for AP treatment.
基金supported by grants from National Natural Science Foundation of China(Grant No.81672932,81874380 and 81730108)Zhejiang Provincial Natural Science Foundation of China for Distinguished Young Scholars(Grant No.LR18H160001)+7 种基金Zhejiang Provincial Natural Science Foundation of China(Grant No.LY15H160028 and LY13H130002)the Science and Technology Development Fund,Macao SAR(130/2017/A3,0099/2018/A3)Zhejiang Province Medical Science and Technology Project(Grant No.2017RC007)Key Project of Zhejiang Province Ministry of Science and Technology(Grant No.2015C03055)Talent Project of Zhejiang Association for Science and Technology(Grant No.2017YCGC002)Zhejiang Province Science and Technology Project of TCM(Grant No.2019ZZ016)Key Project of Hangzhou Ministry of Science and Technology(Grant No.20162013A07,20142013A63)Zhejiang Provincial Project for the Key Discipline of Traditional Chinese Medicine(Grant No.2017-XK-A09)。
文摘Objective:This study aimed to develop a new polyethylene glycol(PEG)ylatedβ-elemene liposome(PEG-Lipo-β-E)and evaluate its characterization,pharmacokinetics,antitumor effects and safety in vitro and in vivo.Methods:The liposomes were prepared by ethanol injection and high-pressure micro-jet homogenization.Characterization of the liposomes was conducted,and drug content,entrapment efficiency(EE),in vitro release and stability were studied by ultra-fast liquid chromatography(UFLC)and a liquid surface method.Blood was drawn from rats to establish the pharmacokinetic parameters.The anticancer effect was evaluated in a KU-19-19 bladder cancer xenograft model.Histological analyses were performed to evaluate safety.Results:The PEG-Lipo-β-E showed good stability and was characterized as 83.31±0.181 nm in size,0.279±0.004 in polydispersity index(PDI),-21.4±1.06 mV in zeta potential,6.65±0.02 in pH,5.024±0.107 mg/mL inβ-elemene(β-E)content,and 95.53±1.712%in average EE.The Fourier transform infrared spectroscopy(FTIR)and differential scanning calorimetry(DSC)indicated the formation of PEG-Lipo-β-E.Compared to elemene injection,PEG-Lipo-β-E demonstrated a 1.75-fold decrease in clearance,a 1.62-fold increase in half-life,and a 1.76-fold increase in area under the concentration-time curves(AUCs)from 0 hour to 1.5 hours(P<0.05).PEG-Lipo-β-E also showed an enhanced anticancer effect in vivo.Histological analyses showed that there was no evidence of toxicity to the heart,kidney,liver,lung or spleen.Conclusions:The present study demonstrates PEG-Lipo-β-E as a new formulation with ease of preparation,high EE,good stability,improved bioavailability and antitumor effects.
基金funded by Shanghai Henlius Biotech, Inc., Science and Technology Commission of Shanghai Municipality (No. 14431908500)China National Major Project for New Drug Innovation (No. 2012ZX09303012)。
文摘Objective: This study aimed to compare the pharmacokinetic, pharmacodynamic and safety profiles of HLX01(a rituximab biosimilar) and reference rituximab sourced from China(Mab Thera?;rituximab-CN).Methods: Here we report the results of two phase 1 studies. In the phase 1 a, open-label, dose-escalation study(NCT03218072, CTR20140400), eligible patients received 250, 375 and 500 mg/m^(2) HLX01 sequentially at 7-day intervals, after confirming no dose-limiting toxicity(DLT). In the phase 1 b, double-blind study(NCT02584920,CTR20140764), eligible patients were given a single dose of 375 mg/m^(2) HLX01 or rituximab-CN. The primary endpoints included safety and tolerability parameters for the phase 1 a and the area under the plasma concentrationtime curve from time zero to day 91(AUC0-91 d) for the phase 1 b study. Equivalence was concluded if 90%confidence interval(90% CI) for the geometric least squares mean ratio(GLSMR) fell in the pre-specified equivalence criteria(80%-125%).Results: Between June 20, 2014 and January 5, 2015, 12 patients were enrolled in the phase 1 a study. The pharmacokinetics of HLX01 showed dose proportionality and accumulation to steady state. HLX01 was well tolerated, with no serious adverse events(AEs), discontinuations or DLTs. Between November 8, 2014 and August13, 2015, 87 eligible patients were enrolled in the phase 1 b study, including 43 who received HLX01 and 44 who were treated with rituximab-CN. The equivalence endpoint was met with GLSMR for AUC0-91 d being 89.6%(90% CI: 80.4%-99.8%). AEs, anti-drug antibodies, and CD19+ and CD20+ B lymphocyte counts were similar between the HLX01 and rituximab-CN treatment groups.Conclusions: Treatment with HLX01 was safe and well tolerated in Chinese patients with B-cell lymphoma.HLX01 and rituximab-CN have similar pharmacokinetic, pharmacodynamic and safety profiles.
基金supported by the National Natural Science Foundation of China (grant numbers 81773691,81703815)Wenzhou Science and Technology Major Project,China (grant number ZS2017018)
文摘Jervine,a novel steroidal alkaloid from Veratrum nigrum L.,exhibits both antitumor effect and potential toxicity.The aim of study was to characterize the pharmacokinetic behaviors and enterohepatic circulation of jervine in rats.A rapid and simple ultra-high performance liquid chromatography-tandem mass spectrometric method was developed and validated for quantification of jervine and alpinetin (internal standard) in rat plasma.After extraction from rat plasma by a simple protein-precipitation method,the analyte was separated on a C18 column (2.1 mm×50 mm,1.7μm) using water with 0.1%formic acid and acetonitrile as the mobile phase delivered at a flow rate of 0.4mL/min.Jervine and alpinetin were determined in the positive mode with multiple reaction monitoring (MRM) of the ion transitions at m/z426.3→108.8 and m/z 271.0 166.9,respectively.Molecular docking method was used to investigate the binding of jervine to p-glycoprotein and dehydroepiandrosterone sulfotransferase.The method was well validated within acceptance limits including specificity,matrix effect,recovery,precision,accuracy,and stability,and was successfully applied to the pharmacokinetic study of jervine after oral and intravenous administration to rats.Jervine presented a small volume of distribution,fast absorption,high oral bioavailability,and enterohepatic circulation.The enterohepatic circulation was first observed in veratrum alkaloids,and was further investigated by molecular docking studies,which was related to the binding of jervine to p-glycoprotein and dehydroepiandrosterone sulfotransferase.The pharmacokinetic properties and enterohepatic circulation of jervine in rats provided a significant basis for the drug-drug interaction and toxicity study in the future.
文摘Timataxel(13-(N-Boc-3-i-butylisoserinoyl-4,10-β-diacetoxy-2-α-benzoyloxy-5-β-20-epoxy-1,13-α-dihydroxy-9-oxo-19-norcyclopropa[g]tax-11-ene)), used to be called TM-2, is a novel semi-synthetic promising candidate for cancer treatment. However the preformulation study showed that TM-2 was insoluble and chemically instable in water, which would limit its application. This study aimed at the preparation of Timataxel lipid microspheres(TM-2 LMs)and investigated the difference between TM-2 LMs and TM-2 solution in pharmacokinetics. In this work, the final formulation was as follows: 0.10%(w/v) TM-2;10.00%(w/v) oil phase(long chain triglyceride:media chain triglyceride = 2.50%:7.50%);1.40%(w/v) phospholipid;0.02%(w/v) NaH2 PO4;2.25%(w/v) glycerin and water to a total volume of 100 ml.The particle size distribution, content and entrapment efficacy were 205.0 ± 43.3 nm, 101.00% and 99.12%, respectively. TM-2 LMs were stable during storage at 25 °C for 3 months, even under the condition of 60 °C and 4500 lx for 10 d. Phosphatidylethanolamine(PE) in phospholipid may contribute to the stability of TM-2 LMs. The pharmacokinetic parameters for TM-2 LMs were as follows: AUC(0-∞) 3663.71 μg/l h and the clearance 2.26 l/h/kg. As for solution, these parameters were 1712.52 μg/l h and 4.77 l/h/kg, respectively. The t1/2 of TM-2 LMs was similar to TM-2 solution. The pharmacokinetic results indicated that the AUC of TM-2 LMs was larger, the clearance was smaller than that of TM-2 solution. In a word, lipid microspheres were a promising drug delivery system for TM-2.
基金Supported by Overall Innovation Plan Projects of Science and Technology of Shaanxi Province in China(2015KTZDSF02-01-02)
文摘OBJECTIVE To determine the characterization,anti-tumor efficacy and pharmacokinetics of bufalin-loaded PEGylated liposomes compared with bufalin entity.METHODS Bufalin-loaded PEGylated liposomes and bufalin-loaded liposomes were prepared reproducibly with homogeneous particle size by the combination of thin film evaporation method and high pressure homogenization method.The particle size and zeta potential of the liposomes were determined by dynamic light scattering technique.The direct imaging of morphology of liposomes was charactered by transmission electron microscope.The content of bufalin in liposomes was analysed by HPLC method.The entrapment efficiency and the particle size was applied to assess the stability profile,after storage at 4℃ on day 0,7,15,30 and 90.The in-vitro release behaviours of bufalin from liposomes were conducted using dialysis bag technique at 37℃.In-vitro cytotoxicity studies were carried out using MTT[3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]assay on several kinds of tumor cel lines including SW620,PC-3,MDA-MB-231,A549,U251,U87 and HepG2.In-vivo pharmacokinetic study of bufalin liposomes was evaluated by HPLC method.RESULTS Their mean particle sizes were 127.6 nm and 155.0 nm,mean zeta potentials were 2.24 m V and-18.5 m V,entrapment efficiencies were 76.31%and 78.40%,respectively.In-vitro release profile revealed that the release of bufalin in bufalin-loaded PEGylated liposomes was slower than that of bufalin-loaded liposomes.The cytotoxicity of blank liposomes has been found within acceptable range,whereas bufalin-loaded PEGylated liposomes showed enhanced cytotoxicity to U251 cells compared with bufalin entity.In-vivo pharmacokinetics indicated that bufalinloaded PEGylated liposomes could extend eliminate half-life time of bufalin in plasma in rats.CONCLUSION The results suggested that bufalin-loaded PEGylated liposomes improved the solubility and increased the drug concentration in plasma.
基金supported by the Major National Scientific Research Projects (2015CB932103)
文摘A pH-responsive conjugate based 10-hydroxycamptothecin-thiosemicarbazide-polyethene glycol 2000 (10-HCPT-hydro-PEG) nano-micelles were prepared in our previous study. In the present study, ultra-performance liquid chromatography (UPLC-MS) method is developed to investigate its pharmacokinetics and biodistribution in tumor bearing mice. The results demonstrated that the conjugate circulated for a much longer time in the blood circulation system than commercial 10-HCPT injection, and bioavailability was significantly improved compared with 10-HCPT. In vivo biodistribution study showed that the conjugate could enhance the targeting and residence time in tumor site.
文摘One purpose of this study was to develop a paliperidone(PAL)tri-layer ascending release pushepull osmotic pump(TA-PPOP)tablet which could meet the needs of clinical applications.And another purpose was to investigate whether different coating materials influenced in vivo performance of TA-PPOP.The ascending release mechanism of this trilayer delivery system on theory was elaborated.TA-PPOP was prepared by means of coating with cellulose acetate(CA)or ethyl cellulose(EC).Several important influence factors such as different core tablet compositions and different coating solution ingredients involved in the formulation procedure were investigated.The optimization of formulation and process was conducted by comparing different in vitro release behaviors of PAL.In vitro dissolution studies indicated that both the two formulations of different coating materials were able to deliver PAL at an ascending release rate during the whole 24 h test.The in vivo pharmacokinetics study showed that both self-made PPOP tablets with different coating had a good in vitro-in vivo correlation(IVIVC)and were bioequivalent with the brand product,which demonstrated no significant influence of the coating materials on the in vivo release acceleration of TA-PPOP.
文摘The aim of the present study was to develop a novel long-acting Poly(lactic-co-glycolic acid)(PLGA)-based microspheres formulation of Bisdemethoxycurcum(BDMC) by emulsionsolvent evaporation method. Meanwhile, the effects of the volume ratio of the dispersed phase and continuous phase, the concentration of PLGA and PVA, the theoretical drug loading and stirring speed were investigated. The mean diameter of the microspheres was 8.5 μm and the size distribution was narrow. The encapsulation efficiency(EE) and drug loading efficiency(DLE) of BDME loaded PLGA microspheres(BDMC-PLGA-MS) was 94.18% and 8.14%,respectively. In an in vitro study of drug release, it can be concluded that the BDMC-PLGAMS exhibited sustained and long-term release properties for 96 h. Stability studies suggested that the microspheres we prepared had a very good stability. Furthermore, the results of an in vivo study indicated that the BDMC-PLGA-MS had sustained release effect and was mainly distributed in the lung tissue, and less distribution in other tissues, which indicated that microspheres could be an effective parenteral carrier for the delivery of BDMC in lung cancer treatment.
文摘Significant progress has been made in understanding pharmacokinetics (PK),pharmacodynamics (PD),as well as toxicity profiles of therapeutic proteins in animals and humans,which have been in commercial development for more than three decades.However,in the PK arena,many fundamental questions remain to be resolved.Investigative and bioanalytical tools need to be established to improve the translation of PK data from animals to humans,and from in vitro assays to in vivo readouts,which would ultimately lead to a higher success rate in drug development.In toxicology,it is known,in general,what studies are needed to safely develop therapeutic proteins,and what studies do not provide relevant information.One of the major complicating factors in nonclinical and clinical programs for therapeutic proteins is the impact of immunogenicity.In this review,we will highlight the emerging science and technology,as well as the challenges around the pharmacokinetic-and safety-related issues in drug development of mAbs and other therapeutic proteins.
文摘This work was done to investigate succinylated commercial whey protein isolate(S-WPI)as an oral sustained-release delivery carrier for puerarin 5(PR-5). The succinylation condi-tions were established for S-WPIs by optimization of single factor study and Box–Beehnkendesign. The effect of succinylation degree on S-WPIs solubility was evaluated. Physicochem-ical properties of S-WPIs dried by different three methods on their flow ability, particle size,morphology and in vitro release behavior were studied. After preparing PR-5 sustained re-lease protein tablets with S-WPIs as the carrier by direct powder compression method, thedrug release were studied in vitro and the oral pharmacokinetics and bioavailability wasevaluated using in vivo dog model. It was observed that concentration of substrate has asignificant effect on succinylation. Release behavior in vitro showed spry dried S-WPIs with100% succinylation rate and 30% drug loading would be applied to the preparation of PR-5 sustained-release protein tablets based on the swelling mechanism(protein loss). Comparedwith PR-5 conventional tablet with oral administration, T max value of PR-5 sustained-releaseprotein tablets was approximately 1.58 fold greater than those of the conventional tablets asfurther evidenced by the significantly prolonged MRT and T 1/2. The findings demonstratedthat spray-dried S-WPIs has potential as a promising functional excipient for the design of PR-5 oral sustained-release tablets which can fully improve sustained-release effect and oral bioavailability.
基金supported by the Natural Science Foundation of Shandong Province,P. R. China (No. ZR2019QC015)the National Key R&D Program of China (No. 2019YFD0900403)+3 种基金the Central Public-Interest Scientific Institution Basal Research Fund,CAFS (Nos. 2019ZD09 03 and 2020TD46)the Marine S&T Fund of Shandong Province for Pilot National Laboratory for Marine Science and Technology (Qingdao)(No. 2018SDKJ0502-2)the Earmarked Fund for Modern Agro-industry Technology Research System (No. CARS-48)the National Natural Science Foundation of China (No. 31873039)。
文摘Adenosine triphosphate-binding cassette transporter breast cancer resistance protein(BCRP) exists highly in the apical membranes of epithelia, and is involved in drug availability. Ko143 is a typical inhibitor of BCRP in rodents. The synthetic antibacterial agent enrofloxacin(ENRO) is a fluoroquinolone employed as veterinary and aquatic medicine, and also a substrate for BCRP. BCRP gene highly expressed in the hepatopancreas and intestine of Exopalaemon carinicauda as was determined with real-time quantitative reverse transcription-polymerase chain reaction(RT-q PCR) method. The effects of Ko143 on the abundance of BCRP m RNA and ENRO pharmacokinetics in E. carinicauda were studied. The m RNA abundance of BCRP decreased significantly in hepatopancreas and intestine(P < 0.05) after Ko143 treatment. Co-administration of Ko143 significantly changed the pharmacokinetics of orally administered enrofloxacin, which was supported by higher distribution half-life(t_(1/2α)), elimination half-life(t_(1/2β)), area under the curve up to the last measurable concentration(AUC_(0-t)), peak concentration(C_(max)) and lower clearance(CL/F). These findings revealed that Ko143 downregulates BCRP expression in hepatopancreas and intestine, thus affects the pharmacokinetics of orally administered enrofloxacin in E. carinicauda. The drug-drug interaction can be caused by the change in BCRP activity if ENRO is used in combination with other drugs in shrimp.
