PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PE-Gylated small-molecule...PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PE-Gylated small-molecule prodrugs have received regulatory approval.This technological gap can be partially attributed to the exponential proliferation of metabolic intermediates resulting from multi-payload conjugation strategies,which introduces unprecedented analytical complexities in metabolite profiling and pharmacokinetic characterization.To address this challenge,we developed a liquid chromatographytriple-quadrupole/time-of-flight mass spectrometry platform for PEG20k-(irinotecan)3,a Phase Ⅲ clinical candidate.Our methodology employs payload stoichiometry-based chromatographic resolution for clustering isomeric PEG species.Complementarily,diagnostic product ions at m/z 699.83,569.27,and 587.28enable systematic differentiation between double-loaded,single-loaded,and released irinotecan payload.This approach successfully identifies eight metabolic clusters spanning from PEG-conjugates,cleaved PEG segments,and released small-molecule species.Its demonstrated capacity to deconvolute complex metabolic profiles-through payload-stoichiometry based chromatographic resolution coupled with diagnostic ion analysis-positions this workflow as an attractive tool for accelerating the development of PE-Gylated small-molecule therapeutics.展开更多
BACKGROUND Ulcerative colitis(UC)is a chronic inflammatory condition requiring continuous treatment and monitoring.There is limited pharmacokinetic data on vedolizumab during maintenance therapy and the effect of thio...BACKGROUND Ulcerative colitis(UC)is a chronic inflammatory condition requiring continuous treatment and monitoring.There is limited pharmacokinetic data on vedolizumab during maintenance therapy and the effect of thiopurines on vedolizumab trough concentrations is unknown.AIM To investigate the exposure-response relationship of vedolizumab and the impact of thiopurine withdrawal in UC patients who have achieved sustained clinical and endoscopic remission during maintenance therapy.METHODS This is a post-hoc analysis of prospective randomized clinical trial(VIEWS)involving UC patients across 8 centers in Australia from 2018 to 2022.Patients in clinical and endoscopic remission were randomized to continue or withdraw thiopurine while receiving vedolizumab.We evaluated vedolizumab serum trough concentrations,presence of anti-vedolizumab antibodies,and clinical outcomes over 48 weeks to assess exposure-response asso-ciation and impact of thiopurine withdrawal.RESULTS There were 62 UC participants with mean age of 43.4 years and 42%were females.All participants received vedolizumab as maintenance therapy with 67.7%withdrew thiopurine.Vedolizumab serum trough concentrations remained stable over 48 weeks regardless of thiopurine use,with no anti-vedolizumab antibodies detected.Pa-tients with clinical remission had higher trough concentrations at week 48.In quartile analysis,a threshold of>11.3μg/mL was associated with sustained clinical remission,showing a sensitivity of 82.4%,specificity of 60.0%,and an area of receiver operating characteristic of 0.71(95%CI:0.49-0.93).Patients discontinuing thiopurine required higher vedolizumab concentrations for achieving remission.CONCLUSION A positive exposure-response relationship between vedolizumab trough concentrations and UC outcomes suggests that monitoring drug levels may be beneficial.While thiopurine did not influence vedolizumab levels,its with-drawal may necessitate higher vedolizumab trough concentrations to maintain remission.展开更多
Background:In a previous study,we found that Atractylodes macrocephala and Paeoniae radix(AM-PR)was useful for the alleviation of functional constipation(FC).However,the precise mechanism underlying the compatibility ...Background:In a previous study,we found that Atractylodes macrocephala and Paeoniae radix(AM-PR)was useful for the alleviation of functional constipation(FC).However,the precise mechanism underlying the compatibility between AM and PR in the treatment of FC remains uncertain.This study aims to analyze the pharmacokinetic differences in the active ingredients in the blood of rat models with FC when applied individually and in combination with AM-PR.It also seeks to compare the changes in the content of the active ingredient when applied individually and in combination with in vitro AM-PR,further in-depth investigation into its material foundation in terms of pharmacokinetics,as well as the composition of the substance.Methods:Blood microdialysis samples were collected using microdialysis technology.These samples from rats with FC were compared after administration of AM,PR,and AM-PR.The concentration of the main active ingredients was determined using the Ultra Performance Liquid Chromatography-Tunable Ultraviolet(UPLC-TUV)method.The concentration of the main active ingredients of the decoction compatibility before and after combining AM-PR was also determined using the UPLC-TUV method.Results:Our findings reveal that upon combination,the time to maximum concentration(T_(max))of isochlorogenic acid A(ICA-A)and ataridolide Ⅱ(ATR-Ⅱ)T_(max)was prolonged,terminal elimination half-life(T_(1/2))was reduced,and maximum plasma concentrations(C_(max))increased.The T_(max)of ataridolide Ⅲ(ATR-Ⅲ)remained consistent,whereas its T_(1/2)and C_(max)were significantly reduced.Conversely,for peoniflorin(PAE),T_(max)occurred sooner,T_(1/2)was shortened,and C_(max)increased.The T_(max)for albiflorin(ALB)remained consistent,whereas T_(1/2)and C_(max)witnessed significant increases.The area under the moment curve(AUMC)(0-t)and AUMC(0-∞)of PAE,ALB,ICA-A,ATR-Ⅱ experienced an increase after AM-PR administration in rats,attributable to the heightened C_(max).In comparison to individual herb administration,the T_(max)of ALB was advanced in combination,the T_(max)of PAE remained unchanged,and the T_(max)of ICA-A and ART-Ⅱ was delayed,with an increased area under the concentration-time curve(AUC)(0-t),indicating enhanced C_(max)and bioavailability.Furthermore,the dissolution rates of PAE,ICA-A,and ATR-Ⅱ significantly improved after compatibility.Conclusions:This study partially clarifies the rationale and compatibility of AM-PR in treating FC and offers a new perspective on the pharmacokinetic interactions of AM-PR in FC treatment.展开更多
OBJECTIVE:To investigate whether Jiegeng(Radix Platycodi,RP)has a Yin-Jing potentiating effect on Jingjie(Herba Schizonepetae Tenuifoliae,ST).We investigated the pharmacokinetics and tissue distribution of pulegone,th...OBJECTIVE:To investigate whether Jiegeng(Radix Platycodi,RP)has a Yin-Jing potentiating effect on Jingjie(Herba Schizonepetae Tenuifoliae,ST).We investigated the pharmacokinetics and tissue distribution of pulegone,the active ingredient in ST volatile oil,in rats to verify the scientific validity of the Yin-Jing doctrine,the basic theory of Traditional Chinese Medicine(TCM).METHODS:The volatile oil and aqueous extract of ST were extracted by hydrodistillation.RP's aqueous extract underwent aqueous extraction.After individual and co-administration,we conducted pharmacokinetic and tissue distribution studies on Sprague-Dawley male rats.RESULTS:Peak concentration(Cmax),mean retention time from 0 to∞(MRT0→∞),and area under the curve(AUC0→10),(AUC0→∞)were 1.51,1.14,2.34,and 3.86 times higher in the co-administration group than in the individual administration group,respectively(P<0.05).In addition,half-life(T1/2)was significantly prolonged in the co-administration group(P<0.05).Meanwhile,the clearance and elimination rate constant(Ke)in the co-administration group were significantly lower than those in the individual administration group,just 50%of those in the individual administration group(P<0.05).After co-administration of the drug,the pulegone content in all tissues of the rats was elevated to varying degrees,especially a significant increase in the drug content in lung tissues(P<0.05).CONCLUSION:After co-administration,the retention of pulegone in the body was prolonged,the elimination of pulegone from the body was delayed,and the accumulation of pulegone in the lungs was facilitated.Therefore,using RP as a Yin-Jing drug concoction has a significant cumulative effect of inducing upward mobilization and targeting lung tissues.展开更多
Liver disease(LD)is a global health problem caused by multiple factors.At present,there are still obvious problems with limited efficacy and strong side effects of drugs used in the clinical treatment of LD.Therefore,...Liver disease(LD)is a global health problem caused by multiple factors.At present,there are still obvious problems with limited efficacy and strong side effects of drugs used in the clinical treatment of LD.Therefore,it is of great significance to search for effective hepatoprotective drugs from natural products.Geniposide(GS)is a cyclic ether terpenoid compound and a key component in the traditional Chinese medicine Gardenia jasminoides.It has a significant inhibitory effect on LD.However,there is currently no literature systematically analyzing its mechanism of action.To adapt to the environment of new drug research and the need for precision medication,this article summarizes the pathways and possible mechanisms of action discovered by GS in the treatment of LD,based on recent research literature:regulating bile stasis,antioxidant and anti-apoptosis,improving amino acid metabolism,improving energy metabolism,regulating lipid metabolism,anti-inflammatory and analgesic effects,etc.It also summarizes the pharmacokinetics of GS in vivo and discusses the liver toxicity of GS that is positively correlated with dosage.In addition,the existing problems in current research and possible future development directions were also discussed,to lay the foundation for the clinical development of natural product GS.展开更多
This study aimed to establish a reliable high-performance liquid chromatography(HPLC)method for determining Voriconazole concentrations in rat plasma,employing an internal standard approach to enhance accuracy.The pha...This study aimed to establish a reliable high-performance liquid chromatography(HPLC)method for determining Voriconazole concentrations in rat plasma,employing an internal standard approach to enhance accuracy.The pharmacokinetics of Voriconazole were also investigated.The method utilized Fluconazole as the internal standard,with gradient elution of a methanol-water mobile phase(0–2.5 min:50%methanol;2.5–4 min:50%–70%methanol;after 4 min:70%methanol).The analysis was performed at 30℃ with a flow rate of 1.0 mL/min,a detection wavelength of 254 nm,and a 20-μL injection volume.Following a single oral dose of Voriconazole(40 mg/kg),plasma concentrations were measured at various time points and analyzed using DAS2.0 software to calculate pharmacokinetic parameters.The method demonstrated excellent linearity(R^(2)=0.9992)over the concentration range of 0.2–40 mg/L.The extraction recoveries ranged from 85%to 115%,and intra-day and inter-day relative standard deviations(RSDs)were below 10%.Pharmacokinetic analysis revealed a distribution half-life of 69.315 min,an elimination half-life of 69.315 min,and an AUC0–t of 8040.73 min·mg/L after oral administration at 40 mg/kg.The proposed HPLC method was simple,rapid,and precise,making it suitable for pharmacokinetic studies of Voriconazole in rats.Furthermore,this method offered potential applicability for clinical batch detection of Voriconazole in blood samples.展开更多
Background:Chiglitazar is a novel pan-agonist that can activate all three subtypes of peroxisome proliferator-activated receptor.It was approved for the treatment of type 2 diabetes mellitus as monotherapy on October ...Background:Chiglitazar is a novel pan-agonist that can activate all three subtypes of peroxisome proliferator-activated receptor.It was approved for the treatment of type 2 diabetes mellitus as monotherapy on October 19,2021,and as combination therapy with metformin when using metformin alone failed in blood glucose control on July 16,2024,by the National Medical Products Administration(NMPA)in China.However,pharmacokinetic(PK)study of this product in patients with renal impairment have not yet been conducted.The purpose of this study is to evaluate the effects of renal impairment on the PK and safety after a single oral dose of Chiglitazar.Methods:This multicenter,open-label,parallel-controlled,single-dose Phase I clinical trial(NCT 05515458)enrolled 24 participants(12/group)with severe renal impairment(SRI)or normal renal function(NRF).All participants received a single oral dose of 48 mg chiglitazar after breakfast and the PK and safety was evaluated.Results:The median Tmax was similar in both SRI and NRF groups(5.01 vs.5.02 hours).The geometric mean ratios(GMR)for Cmax,AUC0-t,and AUC0-∞were 0.807(90%confidence interval[CI]:0.697–0.935),0.853(90%CI:0.713–1.02),and 0.855(90%CI:0.716–1.02),respectively,indicating that SRI did not significantly affect the exposure of chiglitazar.The Cmax was weakly positively correlated with eGFR(r=0.4798,P=0.0177)and creatinine clearance rate(r=0.4667,P=0.0215).Urinary excretion of chiglitazar was negligible in the SRI group,with average values of Ae0-t=2,900 ng,Fe0-t=0.0060%,and CLR=0.323 mL/h within 0–72 hours post-dose.The treatment-emergent adverse event(TEAE)incidence in the SRI group(16.7%,2/12)was comparable to that in the NRF group(25%,3/12).All TEAEs were of mild severity and were adjudicated by the investigators to be unrelated to chiglitazar.No serious AE were reported.Chiglitazar exhibits a favorable safety profile.Conclusion:Severe renal impairment does not significantly affect the PK and safety of chiglitazar,and no dose adjustment for mild,moderate,and severe renal impairments is required.展开更多
Objective:Unlike for drug-drug interactions,rigorous guidelines for assessing herb-drug interactions are nonexistent.GuHong is an intravenous herbal formulation used as adjunct therapy for the management of ischemic s...Objective:Unlike for drug-drug interactions,rigorous guidelines for assessing herb-drug interactions are nonexistent.GuHong is an intravenous herbal formulation used as adjunct therapy for the management of ischemic stroke.This investigation aimed to evaluate its potential to precipitate pharmacokinetic drug interactions.To facilitate the potential assessment,a human multi-compound pharmacokinetic study,along with associated supportive studies,was conducted to pinpoint GuHong compounds for testing.Methods:After analyzing the chemical composition of GuHong,a pharmacokinetic study was conducted in healthy subjects who received GuHong intravenously to identify its significantly exposed compounds and their pharmacokinetics.In addition,supportive rat and in vitro studies were conducted to assess the hepatic and renal disposition of these compounds,including their metabolism and transport.The potential of GuHong to precipitate drug interactions was evaluated in vitro using significantly exposed compounds,which were tested for their effects on drug-metabolizing enzymes and drug transporters listed in the ICH M12 Guideline(2024),with a focus on inhibition and induction.Samples were analyzed by liquid chromatography-mass spectrometry.Results:A total of 54 constituents(0.01-27.18μmol/day)derived from Carthamus tinctorius flowers(Honghua)and N-acetyl-L-glutamine(3,090μmol/day)were detected in GuHong.Following intravenous administration of GuHong,hydroxysafflor yellow A emerged as the principal circulating compound from Honghua.Saffloquinoside D,kaempferol-3-O-rutinoside,kaempferol-3-O-sophoroside,8-hydroxycinnamic acid-8-O-glucoside,coumaric acid-4-O-glucoside,and chlorogenic acid,also from Honghua,were detected but at low plasma levels.Hydroxysafflor yellow A,primarily eliminated via glomerular filtration-based renal excretion,exhibited the characteristics of an intravenous“hard drug.”N-Acetyl-L-glutamine was another major circulating compound of GuHong and was eliminated through renal excretion and hydrolysis to L-glutamine.GuHong had a low potential to precipitate pharmacokinetic drug interactions.Conclusions:The low drug interaction potential of GuHong is advantageous for its use in the treatment of ischemic stroke in the context of polypharmacy.The methodology developed here can be applied to the study of other complex herbal medicines for their pharmacokinetic drug interaction potential.展开更多
This study investigates the pharmacokinetics and metabolic characteristics of three marinederived piericidins as potential drug leads for kidney disease:piericidin A(PA)and its two glycosides(GPAs),glucopiericidin A(G...This study investigates the pharmacokinetics and metabolic characteristics of three marinederived piericidins as potential drug leads for kidney disease:piericidin A(PA)and its two glycosides(GPAs),glucopiericidin A(GPA)and 13-hydroxyglucopiericidin A(13-OH-GPA).The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate.Rapid absorption of PA and GPAs in mice was observed,characterized by short half-lives and low bioavailability.Glycosides and hydroxyl groups significantly enhanced the absorption rate(13-OH-GPA>GPA>PA).PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes(CYPs)and uridine diphosphoglucuronosyl transferases(UGTs).Glucuronidation emerged as the primary metabolic pathway,with UGT1A7,UGT1A8,UGT1A9,and UGT1A10 demonstrating high elimination rates(30%-70%)for PA and GPAs.This rapid glucuronidation may contribute to the low bioavailability of GPAs.Despite its low bioavailability(2.69%),13-OH-GPA showed higher kidney distribution(19.8%)compared to PA(10.0%)and GPA(7.3%),suggesting enhanced biological efficacy in kidney diseases.Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability.In conclusion,this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.展开更多
Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation...Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation into its in vivo pharmacokinetics and tissue distribution is warranted despite its demonstrated biocompatibility and safety.Methods:A UPLC-MS/MS method was established to determine the concentration of euphorbia sterol in rat plasma and mouse tissue homogenates,healthy male SD rats and KM mice were administered in groups,drug concentrations at different time points were determined,pharmacokinetic parameters were analyzed by DAS software,and data were processed by SAS software.Results:The proposed method met the requirements of biological sample detection.The plasma pharmacokinetics of rats showed that the drug concentration in the microsphere group was lower than that in the injection group,and the parameters such as mean residence time(MRT(0–t)),half-life(T1/2z)and apparent volume of distribution(Vz)were significantly different from those in the solution group.The distribution of mouse tissues showed that the drug concentrations in the liver and lung tissues of the microsphere preparation group were higher than those in the injection group,and the drug concentrations in the lung and liver tissues were more distributed.Conclusion:The targeted drug delivery system changed the pharmacokinetic behavior and tissue distribution of euphorbia sterol,slowed down plasma elimination,prolonged the half-life,and improved the targeting of drugs in lung and liver tissues and the magnetic targeting effect of lungs.展开更多
Significant investment in nanocarrier drug delivery systems(Nano-DDSs)has yielded only a limited number of successfully marketed nanomedicines,highlighting a low rate of clinical translation.A primary contributing fac...Significant investment in nanocarrier drug delivery systems(Nano-DDSs)has yielded only a limited number of successfully marketed nanomedicines,highlighting a low rate of clinical translation.A primary contributing factor is the lack of foundational understanding of in vivo processes.Comprehensive knowledge of the pharmacokinetics of Nano-DDSs is essential for developing more efficacious nanomedicines and accurately evaluating their safety and associated risks.However,the complexity of Nano-DDSs has impeded thorough and systematic pharmacokinetic studies.Key components of pharmacokinetic investigations on Nano-DDSs include the analysis of the released drug,the encapsulated drug,and the nanomaterial,which present a higher level of complexity compared to traditional small-molecule drugs.Establishing an appropriate approach for monitoring the pharmacokinetics of Nano-DDSs is crucial for facilitating the clinical translation of nanomedicines.This review provides an overview of advanced bioanalytical methodologies employed in studying the pharmacokinetics of anticancer organic Nano-DDSs over the past five years.We hope that this review will enhance the understanding of the pharmacokinetics of Nano-DDSs and support the advancement of nanomedicines.展开更多
3-(4-Chlorophenyl)-7-[2-(piperazin-1-yl)ethoxy]-4H-chromen-4-one(CPEO-43)is a derivative of soybean isoflavone(SI),synthesized by introducing a chlorine atom and a piperazine group into the structure of natural SI.In ...3-(4-Chlorophenyl)-7-[2-(piperazin-1-yl)ethoxy]-4H-chromen-4-one(CPEO-43)is a derivative of soybean isoflavone(SI),synthesized by introducing a chlorine atom and a piperazine group into the structure of natural SI.In vitro experiments have demonstrated that CPEO-43 exhibits a notable inhibitory effect on both A549 cells and HCT116 cells.For the further development and utilization of CPEO-43,this study aims to establish and validate a liquid chromatography-tandem mass spectrometry(LC-MS/MS)quantitative analysis method for the pharmacokinetic study of CPEO-43.Normal rats were intragastrically administered different doses(2,6,and 20 mg/kg)of CPEO-43,and blood was taken from the ocular venous plexus at different time points.The blood concentration of CPEO-43 at different time points was determined using LC-MS/MS technology,and the pharmacokinetic parameters of the compound were calculated using the pharmacokinetic software DAS.The results indicated that the established LC-MS/MS method complies with the standards for bioanalytical method validation in the Chinese Pharmacopoeia(CHP)and can be applied to the pharmacokinetic study of CPEO-43.The pharmacokinetic software DAS non-compartmental model was successfully used to calculate the C_(max),T_(max),t_(1/2),AUC_(0-∞),MRTs,CL,and Vd pharmacokinetic parameters of the compound at different doses.The results were as follows:62.0±10.5,222.0±28.7,and 1384.5±376.4 ng/mL;8.5±1.2,6.0±0.0,and 11.0±6.2 h;15.6,15.0,and 18.5 h;1517.8±317.0,5328.7±864.4,and 45556.3±22735.6 ng·h/mL;17.8±1.2,17.7±0.8,and 20.0±3.2 h;1370.3±305.9,1153.5±205.6,and 505.3±179.8 mL/kg/h;30843.0±7458.0,24344.0±5237.0,and 13950.3±5996.9 mL/kg.These characteristics are of great significance for understanding the in vivo process of the drug,formulating dosing regimens,and evaluating the safety and efficacy of the drug.展开更多
By analyzing the observed phenomena and the data collected in the study, a multi-compartment linear circulation model for targeting drug delivery system was developed and the function formulas of the drug concentratio...By analyzing the observed phenomena and the data collected in the study, a multi-compartment linear circulation model for targeting drug delivery system was developed and the function formulas of the drug concentration-time in blood and target organ by computing were figured out. The drug concentration-time curve for target organ can be plotted with reference to the data of drug concentration in blood according to the model. The pharmacokinetic parameters of the drug in target organ could also be obtained. The practicability of the model was further checked by the curves of drug concentration-time in blood and target organ(liver) of liver-targeting nanoparticles in animal tests. Based on the liver drug concentration-time curves calculated by the function formula of the drug in target organ, the pharmacokinetic behavior of the drug in target organ(liver) was analyzed by statistical moment, and its pharmacokinetic parameters in liver were obtained. It is suggested that the (relative targeting index( can be used for quantitative evaluation of the targeting drug delivery systems.展开更多
There is an interaction between tacrolimus(TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer.However, the dose of glucocorticoids reported is low but not pulse therapy.We retrospectivel...There is an interaction between tacrolimus(TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer.However, the dose of glucocorticoids reported is low but not pulse therapy.We retrospectively studied 63 renal transplant recipients receiving TAC after transplantation.All the patients were classified as 500 mg(POD 1–3), 30 mg(POD 4–10), 25 mg(POD 11–17), 20 mg(POD 18–24), 15 mg(POD 25–31), 10 mg(POD 32–60) and 10 mg(POD 61–90).We recorded daily data for each patient from the day of transplantation until POD 90.There was no difference in TAC blood levels within the 3 months after transplantation in the glucocorticoids groups.However, the average daily dose of TAC was significantly lower by weekly reductions of 5 mg dose.The TAC daily dose was not changed from POD 1–4, but the blood concentrations of TAC were significantly lower after the glucocorticoid dose was changed from 500 mg to 30 mg.We demonstrated the induction effect of low-dose glucocorticoids on TAC in renal transplant recipients, and found that the high-dose of glucocorticoids might play a role in substrate competition.We proposed that monitoring of the blood concentrations of TAC was needed when the glucocorticoid dose was changed in the patient undergoing renal transplantation.展开更多
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 m...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.展开更多
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 C...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.展开更多
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 ...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.展开更多
Aim To study the pharmacokinetics of oxiracetam after single and multipleintravenous administrations in healthy volunteers. Method A HPLC method was used to determine theserum concentration of oxiracetam after intrave...Aim To study the pharmacokinetics of oxiracetam after single and multipleintravenous administrations in healthy volunteers. Method A HPLC method was used to determine theserum concentration of oxiracetam after intravenous single dose and daily dose of 2 000 mg for 7 din ten Chinese healthy volunteers. Pharmacokinetic analysis was carried out using Drug And Statisticsoftware. Results The AUC_(0-12), AUC_(0-∞), K_e, t_(1/2), MRT after a single dose of 2 000 mgoxiracetam were 256.26 ± 16.84 μg·mL^(-1)·h, 276.74 ±18.11 μg·mL^(-1)·h, 0.18 ±0.03 h^(-1),3.84±0.64 h, and 4.39 10.39 h, and after multiple doses of oxiracetam were 259.36 ±25.43μg·mL^(-1)·h, 285.59 ±27.38 μg·mL^(-1)·h, 0.17 ±0.04 h^(-1), 4.14 ± 0.82 h, and 4.87 ±0.69 h, respectively. Conclusion The pharmacokinetic parameters of oxiracetam do not differremarkably after single and multiple intravenous administration and there is accumulation in serumafter 2 000 mg multiple intravenous administration once a day fof 7 d.展开更多
To evaluate the effect of components in Guanxin Ⅱ prescription on the pharmacokinetic profiles of paeoniflorin. Plasma concentration of Paeoniflorin in rats after intravenous injection of Paronia Pall Extract （PPE）...To evaluate the effect of components in Guanxin Ⅱ prescription on the pharmacokinetic profiles of paeoniflorin. Plasma concentration of Paeoniflorin in rats after intravenous injection of Paronia Pall Extract （PPE） and oral administration of PPE and three types of decoctions in Guanxin Ⅱ prescription, respectively, were determined by HPLC analyses. NONMEM （nonlinear mixed-effect modeling） method was used to analyze full set of pharmacokinetic data directly. A two-compartment model with first-order degradation in absorption compartment was employed for the data analysis. The mean of population parameters, CL1, V1, CL2, V2, Ka0, and Kal, were measured to be 0.509 L/h, 0.104 L, 0.113 L/h, 0.123 L, 0.135/h, and 0.0135/h, respectively. Inter-individual variabilities were estimated and dose formulation （DF） was identified as a significant covariate of Ka 1, Ka0, and V1. It is concluded that the pharmacokinetic behaviors of paeoniflorin in rats can alter with different dose formulations.展开更多
Aim To investigate the population pharmacokinetics of propofol administered by TCI in Chinese elderly patients. Methods Thirty-two patients with ASA Ⅰ - Ⅱ , 65 - 82 years old, undergoing selective lower abdominal op...Aim To investigate the population pharmacokinetics of propofol administered by TCI in Chinese elderly patients. Methods Thirty-two patients with ASA Ⅰ - Ⅱ , 65 - 82 years old, undergoing selective lower abdominal operation were studied. Propofol was administered by target-controlled infusion with Marsh parameter. The target plasma concentration was 3 μg＇ mL^-1. Radial arterial blood samples were collected and analyzed by reversed phase HPLC with fluorescence detection. Population pharmacokinetic modeling was performed using NONMEM. Inter-individual variability and intra-individual variability of propofol were estimated for clearances and volumes of distribution. The effects of age, body weight, lean body mass, gender, height, hemoglobin, total protein, albumin, creatinine, alanine aminotrans ferase （ALT）, and aspartate aminotransferase （AST） were investigated. The effects of coadministered opioid drugs were also studied. Results The pharmacokinetics of propofol in the Chinese elderly patients was best described by a three-compartment open model. Lean body mass was found to be a covariate for system clearance at significant level （ P 〈 0.005）. The clearance decreased linearly with age as well （ P 〈 0. 005）. The apparent volume of distribution for deep peripheral compartment （V3） was influenced by gender. Elderly female patients showed a higher value for V3. Conclusion The pharmacokinetics of propofol administered by TCI in Chinese elderly patients can be well described by a three-compartment open model. Inclusion of age, lean body mass and gender as covariates significantly improved the model. To ensure the accuracy and precision of target-controlled infusion, the population pharmacokinetic model applied to the individual patient should be adjusted reasonably.展开更多
基金support from the National Natural Science Foundation of China(Nos.82030107,82304443,82373944)the Hainan Provincial Natural Science Foundation of China(No.825QN288).
文摘PEGylation,the controlled covalent conjugation of polyethylene glycol to therapeutics,enhances therapeutic efficacy through optimized pharmacokinetics.However,to date no high-molecular-weight PE-Gylated small-molecule prodrugs have received regulatory approval.This technological gap can be partially attributed to the exponential proliferation of metabolic intermediates resulting from multi-payload conjugation strategies,which introduces unprecedented analytical complexities in metabolite profiling and pharmacokinetic characterization.To address this challenge,we developed a liquid chromatographytriple-quadrupole/time-of-flight mass spectrometry platform for PEG20k-(irinotecan)3,a Phase Ⅲ clinical candidate.Our methodology employs payload stoichiometry-based chromatographic resolution for clustering isomeric PEG species.Complementarily,diagnostic product ions at m/z 699.83,569.27,and 587.28enable systematic differentiation between double-loaded,single-loaded,and released irinotecan payload.This approach successfully identifies eight metabolic clusters spanning from PEG-conjugates,cleaved PEG segments,and released small-molecule species.Its demonstrated capacity to deconvolute complex metabolic profiles-through payload-stoichiometry based chromatographic resolution coupled with diagnostic ion analysis-positions this workflow as an attractive tool for accelerating the development of PE-Gylated small-molecule therapeutics.
基金Supported by Takeda Australia,No.IISR-2016-101883.
文摘BACKGROUND Ulcerative colitis(UC)is a chronic inflammatory condition requiring continuous treatment and monitoring.There is limited pharmacokinetic data on vedolizumab during maintenance therapy and the effect of thiopurines on vedolizumab trough concentrations is unknown.AIM To investigate the exposure-response relationship of vedolizumab and the impact of thiopurine withdrawal in UC patients who have achieved sustained clinical and endoscopic remission during maintenance therapy.METHODS This is a post-hoc analysis of prospective randomized clinical trial(VIEWS)involving UC patients across 8 centers in Australia from 2018 to 2022.Patients in clinical and endoscopic remission were randomized to continue or withdraw thiopurine while receiving vedolizumab.We evaluated vedolizumab serum trough concentrations,presence of anti-vedolizumab antibodies,and clinical outcomes over 48 weeks to assess exposure-response asso-ciation and impact of thiopurine withdrawal.RESULTS There were 62 UC participants with mean age of 43.4 years and 42%were females.All participants received vedolizumab as maintenance therapy with 67.7%withdrew thiopurine.Vedolizumab serum trough concentrations remained stable over 48 weeks regardless of thiopurine use,with no anti-vedolizumab antibodies detected.Pa-tients with clinical remission had higher trough concentrations at week 48.In quartile analysis,a threshold of>11.3μg/mL was associated with sustained clinical remission,showing a sensitivity of 82.4%,specificity of 60.0%,and an area of receiver operating characteristic of 0.71(95%CI:0.49-0.93).Patients discontinuing thiopurine required higher vedolizumab concentrations for achieving remission.CONCLUSION A positive exposure-response relationship between vedolizumab trough concentrations and UC outcomes suggests that monitoring drug levels may be beneficial.While thiopurine did not influence vedolizumab levels,its with-drawal may necessitate higher vedolizumab trough concentrations to maintain remission.
基金Natural Science Foundation of Zhejiang Province,Grant/Award Number:Y19H280022。
文摘Background:In a previous study,we found that Atractylodes macrocephala and Paeoniae radix(AM-PR)was useful for the alleviation of functional constipation(FC).However,the precise mechanism underlying the compatibility between AM and PR in the treatment of FC remains uncertain.This study aims to analyze the pharmacokinetic differences in the active ingredients in the blood of rat models with FC when applied individually and in combination with AM-PR.It also seeks to compare the changes in the content of the active ingredient when applied individually and in combination with in vitro AM-PR,further in-depth investigation into its material foundation in terms of pharmacokinetics,as well as the composition of the substance.Methods:Blood microdialysis samples were collected using microdialysis technology.These samples from rats with FC were compared after administration of AM,PR,and AM-PR.The concentration of the main active ingredients was determined using the Ultra Performance Liquid Chromatography-Tunable Ultraviolet(UPLC-TUV)method.The concentration of the main active ingredients of the decoction compatibility before and after combining AM-PR was also determined using the UPLC-TUV method.Results:Our findings reveal that upon combination,the time to maximum concentration(T_(max))of isochlorogenic acid A(ICA-A)and ataridolide Ⅱ(ATR-Ⅱ)T_(max)was prolonged,terminal elimination half-life(T_(1/2))was reduced,and maximum plasma concentrations(C_(max))increased.The T_(max)of ataridolide Ⅲ(ATR-Ⅲ)remained consistent,whereas its T_(1/2)and C_(max)were significantly reduced.Conversely,for peoniflorin(PAE),T_(max)occurred sooner,T_(1/2)was shortened,and C_(max)increased.The T_(max)for albiflorin(ALB)remained consistent,whereas T_(1/2)and C_(max)witnessed significant increases.The area under the moment curve(AUMC)(0-t)and AUMC(0-∞)of PAE,ALB,ICA-A,ATR-Ⅱ experienced an increase after AM-PR administration in rats,attributable to the heightened C_(max).In comparison to individual herb administration,the T_(max)of ALB was advanced in combination,the T_(max)of PAE remained unchanged,and the T_(max)of ICA-A and ART-Ⅱ was delayed,with an increased area under the concentration-time curve(AUC)(0-t),indicating enhanced C_(max)and bioavailability.Furthermore,the dissolution rates of PAE,ICA-A,and ATR-Ⅱ significantly improved after compatibility.Conclusions:This study partially clarifies the rationale and compatibility of AM-PR in treating FC and offers a new perspective on the pharmacokinetic interactions of AM-PR in FC treatment.
基金Supported by Key Laboratory of Xin’an Medicine Open Project Fund(Anhui University of Chinese Medicine)Ministry of Education:Study on the Material Basis and Mechanism of the Buoyance of Jingjie(Herba Schizonepetae Tenuifoliae)Loaded with Jiegeng(Radix Platycodi)of Traditional Chinese Medicine(2020xayx02)Drug Regulatory Scientific Research Key Project:Establishment of a New Dissolution Method Based on Drug Absorption and its Application in Drug Quality Monitoring(AHYJ-KJ-202206,Central of Regulatory Science for Medical Products,Anhui Province)Anhui Provincial Natural Science Foundation of Anhui Province of China:to Explore the Effect and Mechanism of Immune Escape Nanopreparation Based on"Dont eat me"Signal on Tumor Photodynamic Therapy(2308085MH308)。
文摘OBJECTIVE:To investigate whether Jiegeng(Radix Platycodi,RP)has a Yin-Jing potentiating effect on Jingjie(Herba Schizonepetae Tenuifoliae,ST).We investigated the pharmacokinetics and tissue distribution of pulegone,the active ingredient in ST volatile oil,in rats to verify the scientific validity of the Yin-Jing doctrine,the basic theory of Traditional Chinese Medicine(TCM).METHODS:The volatile oil and aqueous extract of ST were extracted by hydrodistillation.RP's aqueous extract underwent aqueous extraction.After individual and co-administration,we conducted pharmacokinetic and tissue distribution studies on Sprague-Dawley male rats.RESULTS:Peak concentration(Cmax),mean retention time from 0 to∞(MRT0→∞),and area under the curve(AUC0→10),(AUC0→∞)were 1.51,1.14,2.34,and 3.86 times higher in the co-administration group than in the individual administration group,respectively(P<0.05).In addition,half-life(T1/2)was significantly prolonged in the co-administration group(P<0.05).Meanwhile,the clearance and elimination rate constant(Ke)in the co-administration group were significantly lower than those in the individual administration group,just 50%of those in the individual administration group(P<0.05).After co-administration of the drug,the pulegone content in all tissues of the rats was elevated to varying degrees,especially a significant increase in the drug content in lung tissues(P<0.05).CONCLUSION:After co-administration,the retention of pulegone in the body was prolonged,the elimination of pulegone from the body was delayed,and the accumulation of pulegone in the lungs was facilitated.Therefore,using RP as a Yin-Jing drug concoction has a significant cumulative effect of inducing upward mobilization and targeting lung tissues.
基金supported by the National Natural Science Foundation of China Key Project(81830110)。
文摘Liver disease(LD)is a global health problem caused by multiple factors.At present,there are still obvious problems with limited efficacy and strong side effects of drugs used in the clinical treatment of LD.Therefore,it is of great significance to search for effective hepatoprotective drugs from natural products.Geniposide(GS)is a cyclic ether terpenoid compound and a key component in the traditional Chinese medicine Gardenia jasminoides.It has a significant inhibitory effect on LD.However,there is currently no literature systematically analyzing its mechanism of action.To adapt to the environment of new drug research and the need for precision medication,this article summarizes the pathways and possible mechanisms of action discovered by GS in the treatment of LD,based on recent research literature:regulating bile stasis,antioxidant and anti-apoptosis,improving amino acid metabolism,improving energy metabolism,regulating lipid metabolism,anti-inflammatory and analgesic effects,etc.It also summarizes the pharmacokinetics of GS in vivo and discusses the liver toxicity of GS that is positively correlated with dosage.In addition,the existing problems in current research and possible future development directions were also discussed,to lay the foundation for the clinical development of natural product GS.
文摘This study aimed to establish a reliable high-performance liquid chromatography(HPLC)method for determining Voriconazole concentrations in rat plasma,employing an internal standard approach to enhance accuracy.The pharmacokinetics of Voriconazole were also investigated.The method utilized Fluconazole as the internal standard,with gradient elution of a methanol-water mobile phase(0–2.5 min:50%methanol;2.5–4 min:50%–70%methanol;after 4 min:70%methanol).The analysis was performed at 30℃ with a flow rate of 1.0 mL/min,a detection wavelength of 254 nm,and a 20-μL injection volume.Following a single oral dose of Voriconazole(40 mg/kg),plasma concentrations were measured at various time points and analyzed using DAS2.0 software to calculate pharmacokinetic parameters.The method demonstrated excellent linearity(R^(2)=0.9992)over the concentration range of 0.2–40 mg/L.The extraction recoveries ranged from 85%to 115%,and intra-day and inter-day relative standard deviations(RSDs)were below 10%.Pharmacokinetic analysis revealed a distribution half-life of 69.315 min,an elimination half-life of 69.315 min,and an AUC0–t of 8040.73 min·mg/L after oral administration at 40 mg/kg.The proposed HPLC method was simple,rapid,and precise,making it suitable for pharmacokinetic studies of Voriconazole in rats.Furthermore,this method offered potential applicability for clinical batch detection of Voriconazole in blood samples.
文摘Background:Chiglitazar is a novel pan-agonist that can activate all three subtypes of peroxisome proliferator-activated receptor.It was approved for the treatment of type 2 diabetes mellitus as monotherapy on October 19,2021,and as combination therapy with metformin when using metformin alone failed in blood glucose control on July 16,2024,by the National Medical Products Administration(NMPA)in China.However,pharmacokinetic(PK)study of this product in patients with renal impairment have not yet been conducted.The purpose of this study is to evaluate the effects of renal impairment on the PK and safety after a single oral dose of Chiglitazar.Methods:This multicenter,open-label,parallel-controlled,single-dose Phase I clinical trial(NCT 05515458)enrolled 24 participants(12/group)with severe renal impairment(SRI)or normal renal function(NRF).All participants received a single oral dose of 48 mg chiglitazar after breakfast and the PK and safety was evaluated.Results:The median Tmax was similar in both SRI and NRF groups(5.01 vs.5.02 hours).The geometric mean ratios(GMR)for Cmax,AUC0-t,and AUC0-∞were 0.807(90%confidence interval[CI]:0.697–0.935),0.853(90%CI:0.713–1.02),and 0.855(90%CI:0.716–1.02),respectively,indicating that SRI did not significantly affect the exposure of chiglitazar.The Cmax was weakly positively correlated with eGFR(r=0.4798,P=0.0177)and creatinine clearance rate(r=0.4667,P=0.0215).Urinary excretion of chiglitazar was negligible in the SRI group,with average values of Ae0-t=2,900 ng,Fe0-t=0.0060%,and CLR=0.323 mL/h within 0–72 hours post-dose.The treatment-emergent adverse event(TEAE)incidence in the SRI group(16.7%,2/12)was comparable to that in the NRF group(25%,3/12).All TEAEs were of mild severity and were adjudicated by the investigators to be unrelated to chiglitazar.No serious AE were reported.Chiglitazar exhibits a favorable safety profile.Conclusion:Severe renal impairment does not significantly affect the PK and safety of chiglitazar,and no dose adjustment for mild,moderate,and severe renal impairments is required.
基金supported in part by the National Natural Science Foundation of China Grants(82192912 and 82074273)by the National Key R&D Program(“Strategic Scientific and Technological Innovation Cooperation”)Key Project(2022YFE0203600)released by the Ministry of Science and Technology。
文摘Objective:Unlike for drug-drug interactions,rigorous guidelines for assessing herb-drug interactions are nonexistent.GuHong is an intravenous herbal formulation used as adjunct therapy for the management of ischemic stroke.This investigation aimed to evaluate its potential to precipitate pharmacokinetic drug interactions.To facilitate the potential assessment,a human multi-compound pharmacokinetic study,along with associated supportive studies,was conducted to pinpoint GuHong compounds for testing.Methods:After analyzing the chemical composition of GuHong,a pharmacokinetic study was conducted in healthy subjects who received GuHong intravenously to identify its significantly exposed compounds and their pharmacokinetics.In addition,supportive rat and in vitro studies were conducted to assess the hepatic and renal disposition of these compounds,including their metabolism and transport.The potential of GuHong to precipitate drug interactions was evaluated in vitro using significantly exposed compounds,which were tested for their effects on drug-metabolizing enzymes and drug transporters listed in the ICH M12 Guideline(2024),with a focus on inhibition and induction.Samples were analyzed by liquid chromatography-mass spectrometry.Results:A total of 54 constituents(0.01-27.18μmol/day)derived from Carthamus tinctorius flowers(Honghua)and N-acetyl-L-glutamine(3,090μmol/day)were detected in GuHong.Following intravenous administration of GuHong,hydroxysafflor yellow A emerged as the principal circulating compound from Honghua.Saffloquinoside D,kaempferol-3-O-rutinoside,kaempferol-3-O-sophoroside,8-hydroxycinnamic acid-8-O-glucoside,coumaric acid-4-O-glucoside,and chlorogenic acid,also from Honghua,were detected but at low plasma levels.Hydroxysafflor yellow A,primarily eliminated via glomerular filtration-based renal excretion,exhibited the characteristics of an intravenous“hard drug.”N-Acetyl-L-glutamine was another major circulating compound of GuHong and was eliminated through renal excretion and hydrolysis to L-glutamine.GuHong had a low potential to precipitate pharmacokinetic drug interactions.Conclusions:The low drug interaction potential of GuHong is advantageous for its use in the treatment of ischemic stroke in the context of polypharmacy.The methodology developed here can be applied to the study of other complex herbal medicines for their pharmacokinetic drug interaction potential.
基金supported by the Special Project for Marine Economic Development of Department of Natural Resources of Guangdong Province(No.GDNRC[2024]25)National Natural Science Foundation of China(Nos.82274002,U20A20101)+1 种基金Guangdong Local Innovation Team Program(No.2019BT02Y262)Science and Technology Innovation Project of Guangdong Medical Products Administration(Nos.S2021ZDZ042,2023ZDZ06,2024-ZDZ08,2024A1515012477)。
文摘This study investigates the pharmacokinetics and metabolic characteristics of three marinederived piericidins as potential drug leads for kidney disease:piericidin A(PA)and its two glycosides(GPAs),glucopiericidin A(GPA)and 13-hydroxyglucopiericidin A(13-OH-GPA).The research aims to facilitate lead selection and optimization for developing a viable preclinical candidate.Rapid absorption of PA and GPAs in mice was observed,characterized by short half-lives and low bioavailability.Glycosides and hydroxyl groups significantly enhanced the absorption rate(13-OH-GPA>GPA>PA).PA and GPAs exhibited metabolic instability in liver microsomes due to Cytochrome P450 enzymes(CYPs)and uridine diphosphoglucuronosyl transferases(UGTs).Glucuronidation emerged as the primary metabolic pathway,with UGT1A7,UGT1A8,UGT1A9,and UGT1A10 demonstrating high elimination rates(30%-70%)for PA and GPAs.This rapid glucuronidation may contribute to the low bioavailability of GPAs.Despite its low bioavailability(2.69%),13-OH-GPA showed higher kidney distribution(19.8%)compared to PA(10.0%)and GPA(7.3%),suggesting enhanced biological efficacy in kidney diseases.Modifying the C-13 hydroxyl group appears to be a promising approach to improve bioavailability.In conclusion,this study provides valuable metabolic insights for the development and optimization of marine-derived piericidins as potential drug leads for kidney disease.
基金sponsored by the Fundamental Research Funds forthe Central Universities(No.2024-JYB-JBZD-047)High Level Key Discipline Construction of Traditional Chinese Medicine(zyyzdxk-2023272).
文摘Background:Building upon our previous work that developed a folate receptor-mediated,euphaorbia factor L1-loaded PLGA microsphere system integrating active and magnetic targeting for theranostics,further investigation into its in vivo pharmacokinetics and tissue distribution is warranted despite its demonstrated biocompatibility and safety.Methods:A UPLC-MS/MS method was established to determine the concentration of euphorbia sterol in rat plasma and mouse tissue homogenates,healthy male SD rats and KM mice were administered in groups,drug concentrations at different time points were determined,pharmacokinetic parameters were analyzed by DAS software,and data were processed by SAS software.Results:The proposed method met the requirements of biological sample detection.The plasma pharmacokinetics of rats showed that the drug concentration in the microsphere group was lower than that in the injection group,and the parameters such as mean residence time(MRT(0–t)),half-life(T1/2z)and apparent volume of distribution(Vz)were significantly different from those in the solution group.The distribution of mouse tissues showed that the drug concentrations in the liver and lung tissues of the microsphere preparation group were higher than those in the injection group,and the drug concentrations in the lung and liver tissues were more distributed.Conclusion:The targeted drug delivery system changed the pharmacokinetic behavior and tissue distribution of euphorbia sterol,slowed down plasma elimination,prolonged the half-life,and improved the targeting of drugs in lung and liver tissues and the magnetic targeting effect of lungs.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82304443,82030107,and 82373944).
文摘Significant investment in nanocarrier drug delivery systems(Nano-DDSs)has yielded only a limited number of successfully marketed nanomedicines,highlighting a low rate of clinical translation.A primary contributing factor is the lack of foundational understanding of in vivo processes.Comprehensive knowledge of the pharmacokinetics of Nano-DDSs is essential for developing more efficacious nanomedicines and accurately evaluating their safety and associated risks.However,the complexity of Nano-DDSs has impeded thorough and systematic pharmacokinetic studies.Key components of pharmacokinetic investigations on Nano-DDSs include the analysis of the released drug,the encapsulated drug,and the nanomaterial,which present a higher level of complexity compared to traditional small-molecule drugs.Establishing an appropriate approach for monitoring the pharmacokinetics of Nano-DDSs is crucial for facilitating the clinical translation of nanomedicines.This review provides an overview of advanced bioanalytical methodologies employed in studying the pharmacokinetics of anticancer organic Nano-DDSs over the past five years.We hope that this review will enhance the understanding of the pharmacokinetics of Nano-DDSs and support the advancement of nanomedicines.
基金Scientific Research Projects of Hebei North University(Grant No.XJ2024022).
文摘3-(4-Chlorophenyl)-7-[2-(piperazin-1-yl)ethoxy]-4H-chromen-4-one(CPEO-43)is a derivative of soybean isoflavone(SI),synthesized by introducing a chlorine atom and a piperazine group into the structure of natural SI.In vitro experiments have demonstrated that CPEO-43 exhibits a notable inhibitory effect on both A549 cells and HCT116 cells.For the further development and utilization of CPEO-43,this study aims to establish and validate a liquid chromatography-tandem mass spectrometry(LC-MS/MS)quantitative analysis method for the pharmacokinetic study of CPEO-43.Normal rats were intragastrically administered different doses(2,6,and 20 mg/kg)of CPEO-43,and blood was taken from the ocular venous plexus at different time points.The blood concentration of CPEO-43 at different time points was determined using LC-MS/MS technology,and the pharmacokinetic parameters of the compound were calculated using the pharmacokinetic software DAS.The results indicated that the established LC-MS/MS method complies with the standards for bioanalytical method validation in the Chinese Pharmacopoeia(CHP)and can be applied to the pharmacokinetic study of CPEO-43.The pharmacokinetic software DAS non-compartmental model was successfully used to calculate the C_(max),T_(max),t_(1/2),AUC_(0-∞),MRTs,CL,and Vd pharmacokinetic parameters of the compound at different doses.The results were as follows:62.0±10.5,222.0±28.7,and 1384.5±376.4 ng/mL;8.5±1.2,6.0±0.0,and 11.0±6.2 h;15.6,15.0,and 18.5 h;1517.8±317.0,5328.7±864.4,and 45556.3±22735.6 ng·h/mL;17.8±1.2,17.7±0.8,and 20.0±3.2 h;1370.3±305.9,1153.5±205.6,and 505.3±179.8 mL/kg/h;30843.0±7458.0,24344.0±5237.0,and 13950.3±5996.9 mL/kg.These characteristics are of great significance for understanding the in vivo process of the drug,formulating dosing regimens,and evaluating the safety and efficacy of the drug.
文摘By analyzing the observed phenomena and the data collected in the study, a multi-compartment linear circulation model for targeting drug delivery system was developed and the function formulas of the drug concentration-time in blood and target organ by computing were figured out. The drug concentration-time curve for target organ can be plotted with reference to the data of drug concentration in blood according to the model. The pharmacokinetic parameters of the drug in target organ could also be obtained. The practicability of the model was further checked by the curves of drug concentration-time in blood and target organ(liver) of liver-targeting nanoparticles in animal tests. Based on the liver drug concentration-time curves calculated by the function formula of the drug in target organ, the pharmacokinetic behavior of the drug in target organ(liver) was analyzed by statistical moment, and its pharmacokinetic parameters in liver were obtained. It is suggested that the (relative targeting index( can be used for quantitative evaluation of the targeting drug delivery systems.
文摘There is an interaction between tacrolimus(TAC) and glucocorticoids where glucocorticoids is a known CYP3A4 and P-gp inducer.However, the dose of glucocorticoids reported is low but not pulse therapy.We retrospectively studied 63 renal transplant recipients receiving TAC after transplantation.All the patients were classified as 500 mg(POD 1–3), 30 mg(POD 4–10), 25 mg(POD 11–17), 20 mg(POD 18–24), 15 mg(POD 25–31), 10 mg(POD 32–60) and 10 mg(POD 61–90).We recorded daily data for each patient from the day of transplantation until POD 90.There was no difference in TAC blood levels within the 3 months after transplantation in the glucocorticoids groups.However, the average daily dose of TAC was significantly lower by weekly reductions of 5 mg dose.The TAC daily dose was not changed from POD 1–4, but the blood concentrations of TAC were significantly lower after the glucocorticoid dose was changed from 500 mg to 30 mg.We demonstrated the induction effect of low-dose glucocorticoids on TAC in renal transplant recipients, and found that the high-dose of glucocorticoids might play a role in substrate competition.We proposed that monitoring of the blood concentrations of TAC was needed when the glucocorticoid dose was changed in the patient undergoing renal transplantation.
文摘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.
文摘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.
文摘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.
文摘Aim To study the pharmacokinetics of oxiracetam after single and multipleintravenous administrations in healthy volunteers. Method A HPLC method was used to determine theserum concentration of oxiracetam after intravenous single dose and daily dose of 2 000 mg for 7 din ten Chinese healthy volunteers. Pharmacokinetic analysis was carried out using Drug And Statisticsoftware. Results The AUC_(0-12), AUC_(0-∞), K_e, t_(1/2), MRT after a single dose of 2 000 mgoxiracetam were 256.26 ± 16.84 μg·mL^(-1)·h, 276.74 ±18.11 μg·mL^(-1)·h, 0.18 ±0.03 h^(-1),3.84±0.64 h, and 4.39 10.39 h, and after multiple doses of oxiracetam were 259.36 ±25.43μg·mL^(-1)·h, 285.59 ±27.38 μg·mL^(-1)·h, 0.17 ±0.04 h^(-1), 4.14 ± 0.82 h, and 4.87 ±0.69 h, respectively. Conclusion The pharmacokinetic parameters of oxiracetam do not differremarkably after single and multiple intravenous administration and there is accumulation in serumafter 2 000 mg multiple intravenous administration once a day fof 7 d.
基金National Natural Science Foundation (Grant No. 30472165)
文摘To evaluate the effect of components in Guanxin Ⅱ prescription on the pharmacokinetic profiles of paeoniflorin. Plasma concentration of Paeoniflorin in rats after intravenous injection of Paronia Pall Extract （PPE） and oral administration of PPE and three types of decoctions in Guanxin Ⅱ prescription, respectively, were determined by HPLC analyses. NONMEM （nonlinear mixed-effect modeling） method was used to analyze full set of pharmacokinetic data directly. A two-compartment model with first-order degradation in absorption compartment was employed for the data analysis. The mean of population parameters, CL1, V1, CL2, V2, Ka0, and Kal, were measured to be 0.509 L/h, 0.104 L, 0.113 L/h, 0.123 L, 0.135/h, and 0.0135/h, respectively. Inter-individual variabilities were estimated and dose formulation （DF） was identified as a significant covariate of Ka 1, Ka0, and V1. It is concluded that the pharmacokinetic behaviors of paeoniflorin in rats can alter with different dose formulations.
文摘Aim To investigate the population pharmacokinetics of propofol administered by TCI in Chinese elderly patients. Methods Thirty-two patients with ASA Ⅰ - Ⅱ , 65 - 82 years old, undergoing selective lower abdominal operation were studied. Propofol was administered by target-controlled infusion with Marsh parameter. The target plasma concentration was 3 μg＇ mL^-1. Radial arterial blood samples were collected and analyzed by reversed phase HPLC with fluorescence detection. Population pharmacokinetic modeling was performed using NONMEM. Inter-individual variability and intra-individual variability of propofol were estimated for clearances and volumes of distribution. The effects of age, body weight, lean body mass, gender, height, hemoglobin, total protein, albumin, creatinine, alanine aminotrans ferase （ALT）, and aspartate aminotransferase （AST） were investigated. The effects of coadministered opioid drugs were also studied. Results The pharmacokinetics of propofol in the Chinese elderly patients was best described by a three-compartment open model. Lean body mass was found to be a covariate for system clearance at significant level （ P 〈 0.005）. The clearance decreased linearly with age as well （ P 〈 0. 005）. The apparent volume of distribution for deep peripheral compartment （V3） was influenced by gender. Elderly female patients showed a higher value for V3. Conclusion The pharmacokinetics of propofol administered by TCI in Chinese elderly patients can be well described by a three-compartment open model. Inclusion of age, lean body mass and gender as covariates significantly improved the model. To ensure the accuracy and precision of target-controlled infusion, the population pharmacokinetic model applied to the individual patient should be adjusted reasonably.
