A sensitive,rapid,and robust ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)method was established for the first time to quantify agarotriose(A3)in rat plasma,tissues,urine,and feces...A sensitive,rapid,and robust ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)method was established for the first time to quantify agarotriose(A3)in rat plasma,tissues,urine,and feces.A3 and stachyose(internal standard)were separated by a BEH amide column at 65℃under the mobile phase of 10 mmol L^(-1)ammonium ace-tate-acetonitrile(42:58,v/v)with 350µLmin-1.The acquisition of transitions was carried out in multiple reaction monitoring(MRM)pattern operating with positive ionization at m/z 509.16>329.15 for A3 and m/z 689.15>527.11 for stachyose.The linearity ranges of A3 were 10 to 5000nmolL^(-1)for plasma,20 to 10000nmolL^(-1)for tissues,and 40 to 20000nmolL^(-1)for urine and feces.The accuracy and precision ranged from 90.9%to 111.6%and 0.7%to 10.1%,respectively.The stability was between 86.1%and 102.5%.The extraction recovery was consistent and reproducible.The matrix effect ranged from 1.5%to 11.4%.The pharmacokinetic,tissue dis-tribution,and excretion studies were successfully conducted with the validated method.Results showed that A3 could be absorbed by rats,and the absolute bioavailability was 6.7%.Furthermore,it was rapidly distributed in rat tissues and mainly eliminated via feces excretion(67.0%)after oral administration.For intravenous bolus,85.5%was recovered,and renal excretion was the primary path-way(77.6%)for cumulative recovery.展开更多
The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscibl...The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscible media that are in contact under conditions of constant phase volumes, at equilibrium. Its value is not affected by the total system solute mass and it only depends on the total system volume, the phase volumes and the affinity of the solute for the two phases in the system. Using this new concept of the apparent volume of distribution, we were able to demonstrate that under certain conditions compartment volumes in multi-compartment and multi-phasic pharmacokinetic models represent the actual physiological volumes of body fluids accessible by drugs. The classical pharmacokinetic models are now fully explained and can be used to provide accurate estimation of the pharmacokinetic parameters for hydrophilic drugs. In contrast, in the absence of tissue-plasma partition coefficients, lipophilic drugs that do not follow a one-compartment model are unlikely to be adequately described with classical multi-compartment pharmacokinetic models.展开更多
The purpose of the current study was to examine the pharmacokinetic profiles and tissue distribution of clevidipine, an ultra-short-acting calcium antagonist in Beagle dogs and Sprague-Dawley rats, respectively. The p...The purpose of the current study was to examine the pharmacokinetic profiles and tissue distribution of clevidipine, an ultra-short-acting calcium antagonist in Beagle dogs and Sprague-Dawley rats, respectively. The pharmacokinetics and biodistribution of its primary metabolite H 152/81 were also evaluated. Dogs received intravenous infusion of clevidipine at a dose rate of 17 μg/(kg·min), and rats were given intravenous administration of clevidipine at a dose of 5 mg/kg. Dog plasma and rat tissues were collected and assayed by HPLC-MS/MS. It was found that plasma clevidipine quickly reached the steady state concentration. The terminal half-life was short (16.8 min), pointing out a rapid elimination after the end of the infusion. The total clearance was 5 mL/(min·kg). In comparison, plasma concentra- tion of H152/81 was increased more slowly and was significantly higher than that of clevidipine. After intravenous administration, clevidipine was distributed rapidly into all tissues examined, with the high- est concentrations found in the brain, heart and liver. Maximal concentrations of clevidipine were found in most tissues at 10 min post-dosing. However, the proportion of clevidipine distributed in all tissues was quite small (0.042‰) compared to the total administration dose. It was suggested that clevidipine was mainly distributed in blood and it transformed to inactive metabolite raoidlv.展开更多
Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral ro...Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.展开更多
AIM: To compare the pharmacokinetics and tissue distribution of 5-fluorouracil administered intraperitoneally with two isotonic carrier solutions: HAES-steri (neotype 6% hydroxyethyl starch), a novel carrier solution ...AIM: To compare the pharmacokinetics and tissue distribution of 5-fluorouracil administered intraperitoneally with two isotonic carrier solutions: HAES-steri (neotype 6% hydroxyethyl starch), a novel carrier solution with middle molecular weight and physiologic saline (0.9% sodium chloride solution), a traditional carrier solution for intraperitoneal chemotherapy, in rats. METHODS: A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Each group was further randomized according to the intraperitoneal dwell period (1, 3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and quantitated. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high- performance liquid chromatography. RESULTS: The mean volumes remaining in the peritoneal cavity were significantly higher with HAES- steri than those with physiologic saline at 1, 6, 12, 18, and 24 h (P = 0.047, 0.009, 0.005, 0.005 and 0.005 respectively, the percentages of remaining peritoneal fluid volume were 89.9 ± 5.6 vs 83.4 ± 4.9, 79.9 ± 2.8 vs 56.2 ± 15.7, 46.8 ± 5.5 vs 24.7 ± 9.7, 23.0 ± 2.8 vs 0.0 ± 0.0 and 4.2 ± 1.7 vs 0.0 ± 0.0 respectively). Mean concentrations in peritoneal fluid were significantly higher with HAES-steri than those with physiologic saline at 3, 12 and 18 h (P = 0.009, 0.009 and 0.005 respectively, the concentrations were 139.2768 ± 28.2317 mg/L vs mg/L, 11.5427 ± 3.0976 mg/L vs 0.0000 ± 0.0000 mg/L and 4.7724 ± 1.0936 mg/L vs 0.0000 ± 0.0000 mg/L respectively). Mean plasma 5-fluorouracil concentrations in portal vein were significantly higher with HAES-steri at 3, 12, 18 and 24 h (P = 0.009, 0.034, 0.005 and 0.019 respectively, the concentrations were 3.3572 ± 0.8128 mg/L vs 0.8794 ± 0.2394 mg/L, 0.6203 ± 0.9935 mg/L vs 0.0112 ± 0.0250 mg/L, 0.3725 ± 0.3871 mg/L vs 0.0000 ± 0.0000 mg/L, and 0.2469 ± 0.1457 mg/L vs 0.0000 ± 0.0000 mg/L respectively), but significantly lower at 1 h (P = 0.009, the concentrations were 4.1957 ± 0.6952 mg/L vs 7.7406 ± 1.2377 mg/L). There were no significant differences in the plasma 5-fluorouracil in inferior caval vein at each time-point. 5-fluorouracil concentrations were significantly greater with HAES-steri at 18 h in gastric tissue (P = 0.016, the concentrations were 0.9486 ± 0.8173 mg/L vs 030392 ± 0.0316 mg/L), at 18 h in colon (P = 0.009, the concentrations were 0.1730 ± 0.0446 mg/L vs 0.0626 ± 0.0425 mg/L), at 3, 6, 12 and 24 h in liver (P = 0.009, 0.013, 0.034 and 0.013 respectively, the concentrations were 0.6472685 ± 0.5256 mg/L vs 0.1554 ± 0.1043mg/L, 0.8606826 ± 0.7155 mg/L vs 0.0014 ± 0.0029 mg/L, 0.0445 ± 0.0330 mg/L vs 0.0797 ± 0.1005 mg/L and 0.0863 ± 0.0399 mg/L vs 0.0034 ± 0.0075 mg/L respectively) and at 18 h in lung (P = 0.009, the concentrations were 0.0886 ± 0.0668 mg/L vs 0.0094 ± 0.0210 mg/L). There were no differences in 5-fluorouracil concentrations in renal tissue at each time-point. CONCLUSION: The use of intraperitoneal 5-fluoro- uracil with HAES-Steri carrier solution provides a pharmacokinetic advantage for a local-regional killing of residual tumor cells and improve the accumulated penetrability of 5-fluorouracil with decreased systemic toxicity. Further clinical feasibility studies on the use of HAES-steri as carrier solution for intraperitoneal chemotherapy with 5-fluorouracil are warranted.展开更多
Objective To characterize the pharmacokinetics and distribution profiles of deltamethrin in miniature pig tissues by gas chromatography-mass spectrometry (GC-MS). Methods Pharmacokinetics and distribution of deltame...Objective To characterize the pharmacokinetics and distribution profiles of deltamethrin in miniature pig tissues by gas chromatography-mass spectrometry (GC-MS). Methods Pharmacokinetics and distribution of deltamethrin in blood and tissues of 30 miniature pigs were studied by GC-MS after oral administration of deltamethrin (5 mg/kg bw). Data were processed by 3P97 software. Results The serum deltamethrin level was significantly lower in tissues than in blood of miniature pigs.The AUC0-72 h, Cmax, of deltamethrin were 555.330±316.987 ng h/mL and 17.861±11.129 ng/mL, respectively. The Tmax, of deltamethrin was 6.004±3.131 h.Conclusion The metabolism of deltamethrin in miniature pigs is fit for a one-compartment model with a weighting function of I/C^2. Deltamethrin is rapidly hydrolyzed and accumulated in miniature pig tissues.展开更多
Cancer is the leading cause of death all over the world.Among the chemotherapy drugs,taxanes play an important role in cancer treatment.6258-70 is a new semi-synthetic taxane which has a broad spectrum of antitumor ac...Cancer is the leading cause of death all over the world.Among the chemotherapy drugs,taxanes play an important role in cancer treatment.6258-70 is a new semi-synthetic taxane which has a broad spectrum of antitumor activity.A fast and reliable high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS) method was developed for quantification of 6258-70 in rat plasma and tissues in this paper.After extraction by liquid-liquid extraction method with methyl tert-butyl ether,the samples were separated on a Kinetex C_(18) column(50 mm × 2.1 mm,2.6 μm,Phenomenex,USA) within3 min.The method was fully validated with the matrix effect between 87.7%and 99.5%and the recovery ranging from 80.3%to 90.1%.The intra- and inter-day precisions were less than 9.5%and the accuracy ranged from-3.8%to 6.5%.The reliable method was successfully applied to the pharmacokinetics and tissue distribution studies of 6258-70 after intravenous administration in rats.The pharmacokinetic results indicated that the pharmacokinetic behavior of 6258-70 in rats was in accordance with linear features within tested dosage of 1 to 4 mg/kg,and there was no significant difference between the two genders.The tissue distribution study showed that 6258-70 had an effective penetration,spread widely and rapidly and could cross blood-brain barrier.The results of pharmacokinetics and tissue distribution may provide a guide for future study.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 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
In 2015,liposomal formulation of irinotecan(ONIVYDE)has been approved by FDA and widely applied in the treatment of pancreatic cancer.ONIVYDE is a novel liposome formulation,entrapping CPT-11 in the aqueous core of ve...In 2015,liposomal formulation of irinotecan(ONIVYDE)has been approved by FDA and widely applied in the treatment of pancreatic cancer.ONIVYDE is a novel liposome formulation,entrapping CPT-11 in the aqueous core of vesicles using a modified gradient loading method.Due to toxicity concerns,it is essential to explore a rapid and reliable method to effectively isolate and quantify the non-liposomal,namely,free CPT-11and total CPT-11 in plasma.This study focuses on separation of non-liposomal CPT-11,evaluation of the pharmacokinetics of free CPT-11 and total CPT-11 and bio-distribution after intravenous administration of CPT-11 liposome.Free CPT-11 in plasma was separated by solid-phase extraction(SPE).The amount of total CPT-11 and main metabolite 7-ethyl-10-hydroxycamptothecin(SN-38)in plasma was quantified by ultra-performance liquid chromatography–MS/MS.The calibration curves fitted well and lower limit of quantitation for SN-38,free CPT-11,total CPT-11 and CPT-11 in tissue and were 5 ng/ml,10 ng/ml,4.44 ng/ml and 25 ng/ml respectively.The recoveries,precision and accuracy of the method appear satisfactory.Using this method,the pharmacokinetics and bio-distribution of CPT-11 liposome formulation after an intravenous dose of 2.5 mg/kg were then investigated.展开更多
The previous pharmacokinetic methods can be only limited to drug analysis in vitro, which provide less information on the distribution and metabolismof drugs, and limit the interpretation and assessment of pharmacokin...The previous pharmacokinetic methods can be only limited to drug analysis in vitro, which provide less information on the distribution and metabolismof drugs, and limit the interpretation and assessment of pharmacokinetics, the determination of metabolic principles, and evaluation of treatment effect. The objective of the study was to investigate the pharmacokinetic characteristics of gene recombination angiogenesis inhibitor Kringle 5 in vivo. The SPECT/CT and specific^(131)I-Kringle 5 marked by Iodogen method were both applied to explore the pharmacokinetic characteristics of^(131)I-Kringle 5 in vivo, and to investigate the dynamic distributions of^(131)I-Kringle 5 in target organs. Labeling recombinant angiogenesis inhibitor Kringle 5 using131 I with longer half-life and imaging in vivo using SPECT instead of PET,could overcome the limitations of previous methods. When the doses of^(131)I-Kringle 5 were 10.0, 7.5 and5.0 g/kg, respectively, the two-compartment open models can be determined within all the metabolic process in vivo. There were no significant differences in t1/2α, t1/2β, apparent volume of distribution and CL between those three levels. The ratio of AUC(0 1)among three different groups of 10.0, 7.5 and 5.0 g/kg was 2.56:1.44:1.0, which was close to the ratio(2:1.5:1.0). It could be clear that in the range of 5.0–10.0 g/kg, Kringle 5 was characterized by the first-order pharmacokinetics. Approximately 30 min after^(131)I-Kringle 5 was injected,^(131)I-Kringle 5 could be observed to concentrate in the heart, kidneys, liver and other organs by means of planar imaging and tomography. After 1 h of being injected, more radionuclide retained in the bladder, but not in intestinal. It could be concluded that^(131)I-Kringle 5 is mainly excreted through the kidneys. About 2 h after the injection of^(131)I-Kringle 5, the radionuclide in the heart, kidneys,liver and other organs was gradually reduced, while more radionuclide was concentrated in the bladder.The radionuclide was completely metabolized within 24 h, and the distribution of radioactivity in rats was similar to normal levels. In our study, the specific marker^(131)I-Kringle 5 and SPECT/CT were successfully used to explore pharmacokinetic characteristics of Kringle 5 in rats. The study could provide a new evaluation platform of the specific, in vivo and real-time functional imaging and pharmacokinetics for the clinical application of^(131)I-Kringle 5.展开更多
A simple, sensitive ane selective high performance liquid chromatographic (HPLC) method with UV detection (320 nm) was developed and validated for determination of mangiferin in rat plasma and tissues. Mangiferin ...A simple, sensitive ane selective high performance liquid chromatographic (HPLC) method with UV detection (320 nm) was developed and validated for determination of mangiferin in rat plasma and tissues. Mangiferin and internal standard (spinosin) were separated using mobile phase of acetonitrile-water (20:80, v/v) with 1% glacial acetic acid and 1% THF on a Phenomenex gemini C18 column. The flow rate was 0.7 mL/min. The calibration curves of mangiferin in plasma and tissues were linear over the investigated ranges. The intra- and inter-run preeisions for all samples were less than 13.8 %. The time-concentration curve of mangiferin after intravenous administration to rats corresponded to two-compartment model. The main pharmacokinetic parameters T0.5α, T0.5β, CL and AUC0-T were 15.87 min, 26.15 rain, 6.1 L/(min·kg) and 3.28 mg· min/mL, respectively. The highest and lowest levels of mangiferin occurred in spleen and brain, respectively. Mangiferin was not found in liver. After intravenous administration, the drug was distributed extensively and transferred quickly in rats in vivo.展开更多
Alpinia officinarum Hance of the Chinese traditional herb for the treatment of emesis, abdominal pain and diarrhea has been used to counteract gastric disease induced by indomethacin in rats without obvious side effec...Alpinia officinarum Hance of the Chinese traditional herb for the treatment of emesis, abdominal pain and diarrhea has been used to counteract gastric disease induced by indomethacin in rats without obvious side effects. However, the role of herb-drug interaction between indomethacin and A. officinarum based on pharmacokinetic, tissue distribution and excretion still remains unknown. In this study, an ultra-fast liquid-tandem mass spectrometry(UFLC-MS/MS) method was developed for simultaneous determination of indomethacin and its three metabolites, O-desmethylindomethacin(ODI), deschlorobenzoylindomethacin(NDI) and indomethacin acyl-b-D-glucuronide(IDAbG) by oral administration of indomethacin solution with and without the ethanolic extract of A. officinarum and applied to comparative pharmacokinetic, tissue distribution and excretion studies. Our results clarified that oral administration of A. officinarum produced significant alterations in the pharmacokinetic parameters of indomethacin. And the pharmacokinetic interaction between indomethacin and A. officinarum reduced the systemic exposure of indomethacin and increased its elimination. Tissue distribution results demonstrated that co-administration of A. Officinarum could not reduce the accumulation of indomethacin in the target tissue of the stomach, but could accelerate the excretions of indomethacin and its three metabolites including ODI, NDI and IDAb G in the bile and feces of rats in the excretion study.Therefore, A. Officinarum might have a gastrointestinal protective effect through the interaction role with indomethacin based on the pharmacokinetics and excretion in rats.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
Cystine is the primary source material for the synthesis of glutathione.However,the pharmacokinetics and tissue distribution of cystine are largely unknown.A surrogate analyte D_(4)-cystine was employed to generate ca...Cystine is the primary source material for the synthesis of glutathione.However,the pharmacokinetics and tissue distribution of cystine are largely unknown.A surrogate analyte D_(4)-cystine was employed to generate calibration curves for the determination of levels of D_(4)-cystine and endogenous cystine in mice by liquid chromatography-tandem mass spectrometry(LC-MS/MS).Validation assessments proved the sensitivity,specificity and reproducibility of the method with a lower limit of quantification(LLOQ)of 5 ng/mL over 5e5000 ng/mL in plasma.The pharmacokinetics of D_(4)-cystine were evaluated after administering injections and oral solutions,both of which minimally impacted endogenous cystine levels.The absolute bioavailability of cystine was 18.6%,15.1%and 25.6%at doses of 25,50 and 100 mg/kg,respectively.Intravenously injected D_(4)-cystine resulted in dramatically high plasma levels with reduced levels in the brain and liver.Intragastrically administered D_(4)-cystine resulted in high levels in the plasma and stomach with relatively low levels in the lung,kidney,heart and brain.展开更多
[Objectives]To establish an acute yunaconitine poisoning rat model with a single oral administration and to determine the contents of yunaconitine in rat tissues by UPLC-MS/MS method,then investigate the distribution ...[Objectives]To establish an acute yunaconitine poisoning rat model with a single oral administration and to determine the contents of yunaconitine in rat tissues by UPLC-MS/MS method,then investigate the distribution of yunaconitine in rats. [Methods]The rats were randomly divided into three groups and were intragastrically administered a single dose of 2. 2,1. 1,and 0. 7 mg/kg of yunaconitine,respectively.The rats were killed 2 h later,the stomach tissue,intestine tissue,liver tissue,pancreas tissue,kidney tissue,lung tissue,spleen tissue,heart tissue,bladder tissue,testis tissue,brain tissue and heart blood samples were collected. The contents of yunaconitine in the biological materials were determined by UPLC-MS/MS method after the biological samples extracted by liquid-liquid extraction. [Results] A rat model of the yunaconitine poisoning was made with a single dose of 1. 1 mg/kg,the concentrations of yunaconitine shown in the organs with the following order: stomach,small intestine,liver,pancreas,kidney,lung,spleen,heart,bladder,testis,heart blood and brain. [Conclusions]Yunaconitine was widely distributed in rats,especially the levels in the stomach,small intestine and liver were the highest. The conclusion is expected to provide a basis for the selection of test materials for the poisoning of Aconitum vilmorinianum Kom.展开更多
Rotundic acid(RA),an ursane-type pentacyclic triterpene acid isolated from the dried barks of Ilex rotunda Thunb.(Aquifoliaceae),possesses diverse bioactivities.To further study its pharmacokinetics,a simple and sensi...Rotundic acid(RA),an ursane-type pentacyclic triterpene acid isolated from the dried barks of Ilex rotunda Thunb.(Aquifoliaceae),possesses diverse bioactivities.To further study its pharmacokinetics,a simple and sensitive liquid chromatography with triple quadrupole mass spectrometry(LC-QqQ-MS/MS)method was developed and validated to quantify RA concentration in rat plasma and tissue using etofesalamide as an internal standard(IS).Plasma and tissue samples were subjected to one-step protein precipitation.Chromatographic separation was achieved on a ZORBAX Eclipse XDB-C_(18) column(4.6mm×50mm,5μm)under gradient conditions with eluents of methanol:acetonitrile(1:1,V/V)and 5mM ammonium formate:methanol(9:1,V/V)at 0.5mL/min.Multiple reaction monitoring transitions were performed at m/z 487.30→437.30 for RA and m/z 256.10→227.10 for IS in the negative mode.The developed LC-QqQ-MS/MS method exhibited good linearity(2-500 ng/mL)and was fully validated in accordance with U.S.Food and Drug Administration bioanalytical guidelines.Dose proportionality and bioavailability in rats were determined by comparing pharmacokinetic data after single oral(10,20,and 40mg/kg)and intravenous(10mg/kg)administration of RA.Tissue distribution was studied following oral administration at 20mg/kg.The results showed that the absolute bioavailability of RA after administration at different doses ranged from 16.1%to 19.4%.RA showed good dose proportionality over a dose range of 10-40 mg/kg.RA was rapidly absorbed in a dose-dependent manner and highly distributed in the liver.In conclusion,this study is the first to systematically elucidate the absorption and distribution characteristics of RA in rats,which can provide additional information for further development and evaluation of RA in drug metabolism and pharmacokinetic studies.展开更多
Background: The aim of this study was to investigate the distribution of the c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles in the major organs of mice by MR imaging. Methods: Sixty BA...Background: The aim of this study was to investigate the distribution of the c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles in the major organs of mice by MR imaging. Methods: Sixty BALB/c mice were randomly divided into experimental and control groups. MR scans were performed in each mouse of the experimental group at five different time points (10, 30, 60, 180 and 360 min) after injection of the antisense probe. The signal from each major organ (liver, spleen, heart, kidney and muscle tissue) in comparison with the background signal (signal to noise ratio) was determined at each time point as a measure of the distribution of the antisense probe. Six control mice were killed at each of the same time points and the organs immediately removed for determination of their iron content. Results: After injection of the antisense probe, the highest enrichment of the probe was seen in the spleen, reaching a peak at 180 min, followed by the liver, muscle, heart and kidney. Conclusions: MR imaging can visualize the distribution of c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles in the major organs of mice, and this may provide the basis for further in vivo studies of MR imaging time and dose selection.展开更多
基金funded by the Fundamental Research Funds for the Central Universities(Nos.201912008,201964019)the Natural Science Foundation of Shandong Province(No.ZR2019BC025).
文摘A sensitive,rapid,and robust ultra-high performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS)method was established for the first time to quantify agarotriose(A3)in rat plasma,tissues,urine,and feces.A3 and stachyose(internal standard)were separated by a BEH amide column at 65℃under the mobile phase of 10 mmol L^(-1)ammonium ace-tate-acetonitrile(42:58,v/v)with 350µLmin-1.The acquisition of transitions was carried out in multiple reaction monitoring(MRM)pattern operating with positive ionization at m/z 509.16>329.15 for A3 and m/z 689.15>527.11 for stachyose.The linearity ranges of A3 were 10 to 5000nmolL^(-1)for plasma,20 to 10000nmolL^(-1)for tissues,and 40 to 20000nmolL^(-1)for urine and feces.The accuracy and precision ranged from 90.9%to 111.6%and 0.7%to 10.1%,respectively.The stability was between 86.1%and 102.5%.The extraction recovery was consistent and reproducible.The matrix effect ranged from 1.5%to 11.4%.The pharmacokinetic,tissue dis-tribution,and excretion studies were successfully conducted with the validated method.Results showed that A3 could be absorbed by rats,and the absolute bioavailability was 6.7%.Furthermore,it was rapidly distributed in rat tissues and mainly eliminated via feces excretion(67.0%)after oral administration.For intravenous bolus,85.5%was recovered,and renal excretion was the primary path-way(77.6%)for cumulative recovery.
文摘The apparent volume of distribution was defined for the first time as the phase volume that can hold the total amount of a substance at the measured phase substance concentration, in a system composed of two immiscible media that are in contact under conditions of constant phase volumes, at equilibrium. Its value is not affected by the total system solute mass and it only depends on the total system volume, the phase volumes and the affinity of the solute for the two phases in the system. Using this new concept of the apparent volume of distribution, we were able to demonstrate that under certain conditions compartment volumes in multi-compartment and multi-phasic pharmacokinetic models represent the actual physiological volumes of body fluids accessible by drugs. The classical pharmacokinetic models are now fully explained and can be used to provide accurate estimation of the pharmacokinetic parameters for hydrophilic drugs. In contrast, in the absence of tissue-plasma partition coefficients, lipophilic drugs that do not follow a one-compartment model are unlikely to be adequately described with classical multi-compartment pharmacokinetic models.
基金supported in part by the Important National Science & Technology Specific Projects in the 12th Five-year Plan of China(No.2011ZX09302-002-01)
文摘The purpose of the current study was to examine the pharmacokinetic profiles and tissue distribution of clevidipine, an ultra-short-acting calcium antagonist in Beagle dogs and Sprague-Dawley rats, respectively. The pharmacokinetics and biodistribution of its primary metabolite H 152/81 were also evaluated. Dogs received intravenous infusion of clevidipine at a dose rate of 17 μg/(kg·min), and rats were given intravenous administration of clevidipine at a dose of 5 mg/kg. Dog plasma and rat tissues were collected and assayed by HPLC-MS/MS. It was found that plasma clevidipine quickly reached the steady state concentration. The terminal half-life was short (16.8 min), pointing out a rapid elimination after the end of the infusion. The total clearance was 5 mL/(min·kg). In comparison, plasma concentra- tion of H152/81 was increased more slowly and was significantly higher than that of clevidipine. After intravenous administration, clevidipine was distributed rapidly into all tissues examined, with the high- est concentrations found in the brain, heart and liver. Maximal concentrations of clevidipine were found in most tissues at 10 min post-dosing. However, the proportion of clevidipine distributed in all tissues was quite small (0.042‰) compared to the total administration dose. It was suggested that clevidipine was mainly distributed in blood and it transformed to inactive metabolite raoidlv.
文摘Published clinical data of Prazosin were reevaluated pharmacokinetically using explicit solutions to drug concentration as a function of total time for IV bolus injection, intermittent intravenous infusion and oral routes of administration in an open two-compartment model. In a novel way, the apparent volume of distribution was estimated from a two-compartment model and found to be close to the total body water suggesting that Prazosin is distributed in all tissues both extracellularly and intracellularly. In addition, extracting the value of the apparent volume of distribution from a two-compartment model allowed comparative simulations in the one-compartment model. It is shown that dosage calculations of Prazosin intermittent infusion can be safely performed using the simpler one-compartment model equations. Lastly, several additional time-dependent pharmacokinetic parameters e.g., the peak time in the central and peripheral compartment and non-steady state and steady state peak concentration and AUC were determined using series equations for all three routes of administration, as a function of dose number and total time upon multiple drug administrations in the two-compartment model. It is also the first time that steady-state plasma drug concentration equations were derived in a two-compartment mammillary model.
文摘AIM: To compare the pharmacokinetics and tissue distribution of 5-fluorouracil administered intraperitoneally with two isotonic carrier solutions: HAES-steri (neotype 6% hydroxyethyl starch), a novel carrier solution with middle molecular weight and physiologic saline (0.9% sodium chloride solution), a traditional carrier solution for intraperitoneal chemotherapy, in rats. METHODS: A total of 60 Sprague Dawley rats were randomized into groups according to the carrier solution administered. Each group was further randomized according to the intraperitoneal dwell period (1, 3, 6, 12, 18 and 24 h). At the end of the procedure the rats were killed, the peritoneal fluid was withdrawn completely and quantitated. Drug concentrations in peritoneal fluid, plasma, and tissues were determined by high- performance liquid chromatography. RESULTS: The mean volumes remaining in the peritoneal cavity were significantly higher with HAES- steri than those with physiologic saline at 1, 6, 12, 18, and 24 h (P = 0.047, 0.009, 0.005, 0.005 and 0.005 respectively, the percentages of remaining peritoneal fluid volume were 89.9 ± 5.6 vs 83.4 ± 4.9, 79.9 ± 2.8 vs 56.2 ± 15.7, 46.8 ± 5.5 vs 24.7 ± 9.7, 23.0 ± 2.8 vs 0.0 ± 0.0 and 4.2 ± 1.7 vs 0.0 ± 0.0 respectively). Mean concentrations in peritoneal fluid were significantly higher with HAES-steri than those with physiologic saline at 3, 12 and 18 h (P = 0.009, 0.009 and 0.005 respectively, the concentrations were 139.2768 ± 28.2317 mg/L vs mg/L, 11.5427 ± 3.0976 mg/L vs 0.0000 ± 0.0000 mg/L and 4.7724 ± 1.0936 mg/L vs 0.0000 ± 0.0000 mg/L respectively). Mean plasma 5-fluorouracil concentrations in portal vein were significantly higher with HAES-steri at 3, 12, 18 and 24 h (P = 0.009, 0.034, 0.005 and 0.019 respectively, the concentrations were 3.3572 ± 0.8128 mg/L vs 0.8794 ± 0.2394 mg/L, 0.6203 ± 0.9935 mg/L vs 0.0112 ± 0.0250 mg/L, 0.3725 ± 0.3871 mg/L vs 0.0000 ± 0.0000 mg/L, and 0.2469 ± 0.1457 mg/L vs 0.0000 ± 0.0000 mg/L respectively), but significantly lower at 1 h (P = 0.009, the concentrations were 4.1957 ± 0.6952 mg/L vs 7.7406 ± 1.2377 mg/L). There were no significant differences in the plasma 5-fluorouracil in inferior caval vein at each time-point. 5-fluorouracil concentrations were significantly greater with HAES-steri at 18 h in gastric tissue (P = 0.016, the concentrations were 0.9486 ± 0.8173 mg/L vs 030392 ± 0.0316 mg/L), at 18 h in colon (P = 0.009, the concentrations were 0.1730 ± 0.0446 mg/L vs 0.0626 ± 0.0425 mg/L), at 3, 6, 12 and 24 h in liver (P = 0.009, 0.013, 0.034 and 0.013 respectively, the concentrations were 0.6472685 ± 0.5256 mg/L vs 0.1554 ± 0.1043mg/L, 0.8606826 ± 0.7155 mg/L vs 0.0014 ± 0.0029 mg/L, 0.0445 ± 0.0330 mg/L vs 0.0797 ± 0.1005 mg/L and 0.0863 ± 0.0399 mg/L vs 0.0034 ± 0.0075 mg/L respectively) and at 18 h in lung (P = 0.009, the concentrations were 0.0886 ± 0.0668 mg/L vs 0.0094 ± 0.0210 mg/L). There were no differences in 5-fluorouracil concentrations in renal tissue at each time-point. CONCLUSION: The use of intraperitoneal 5-fluoro- uracil with HAES-Steri carrier solution provides a pharmacokinetic advantage for a local-regional killing of residual tumor cells and improve the accumulated penetrability of 5-fluorouracil with decreased systemic toxicity. Further clinical feasibility studies on the use of HAES-steri as carrier solution for intraperitoneal chemotherapy with 5-fluorouracil are warranted.
基金supported by the National Natural Science Foundation of China,No.30700664 and No.2012CB720804
文摘Objective To characterize the pharmacokinetics and distribution profiles of deltamethrin in miniature pig tissues by gas chromatography-mass spectrometry (GC-MS). Methods Pharmacokinetics and distribution of deltamethrin in blood and tissues of 30 miniature pigs were studied by GC-MS after oral administration of deltamethrin (5 mg/kg bw). Data were processed by 3P97 software. Results The serum deltamethrin level was significantly lower in tissues than in blood of miniature pigs.The AUC0-72 h, Cmax, of deltamethrin were 555.330±316.987 ng h/mL and 17.861±11.129 ng/mL, respectively. The Tmax, of deltamethrin was 6.004±3.131 h.Conclusion The metabolism of deltamethrin in miniature pigs is fit for a one-compartment model with a weighting function of I/C^2. Deltamethrin is rapidly hydrolyzed and accumulated in miniature pig tissues.
文摘Cancer is the leading cause of death all over the world.Among the chemotherapy drugs,taxanes play an important role in cancer treatment.6258-70 is a new semi-synthetic taxane which has a broad spectrum of antitumor activity.A fast and reliable high performance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS) method was developed for quantification of 6258-70 in rat plasma and tissues in this paper.After extraction by liquid-liquid extraction method with methyl tert-butyl ether,the samples were separated on a Kinetex C_(18) column(50 mm × 2.1 mm,2.6 μm,Phenomenex,USA) within3 min.The method was fully validated with the matrix effect between 87.7%and 99.5%and the recovery ranging from 80.3%to 90.1%.The intra- and inter-day precisions were less than 9.5%and the accuracy ranged from-3.8%to 6.5%.The reliable method was successfully applied to the pharmacokinetics and tissue distribution studies of 6258-70 after intravenous administration in rats.The pharmacokinetic results indicated that the pharmacokinetic behavior of 6258-70 in rats was in accordance with linear features within tested dosage of 1 to 4 mg/kg,and there was no significant difference between the two genders.The tissue distribution study showed that 6258-70 had an effective penetration,spread widely and rapidly and could cross blood-brain barrier.The results of pharmacokinetics and tissue distribution may provide a guide for future study.
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.
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.
文摘In 2015,liposomal formulation of irinotecan(ONIVYDE)has been approved by FDA and widely applied in the treatment of pancreatic cancer.ONIVYDE is a novel liposome formulation,entrapping CPT-11 in the aqueous core of vesicles using a modified gradient loading method.Due to toxicity concerns,it is essential to explore a rapid and reliable method to effectively isolate and quantify the non-liposomal,namely,free CPT-11and total CPT-11 in plasma.This study focuses on separation of non-liposomal CPT-11,evaluation of the pharmacokinetics of free CPT-11 and total CPT-11 and bio-distribution after intravenous administration of CPT-11 liposome.Free CPT-11 in plasma was separated by solid-phase extraction(SPE).The amount of total CPT-11 and main metabolite 7-ethyl-10-hydroxycamptothecin(SN-38)in plasma was quantified by ultra-performance liquid chromatography–MS/MS.The calibration curves fitted well and lower limit of quantitation for SN-38,free CPT-11,total CPT-11 and CPT-11 in tissue and were 5 ng/ml,10 ng/ml,4.44 ng/ml and 25 ng/ml respectively.The recoveries,precision and accuracy of the method appear satisfactory.Using this method,the pharmacokinetics and bio-distribution of CPT-11 liposome formulation after an intravenous dose of 2.5 mg/kg were then investigated.
文摘The previous pharmacokinetic methods can be only limited to drug analysis in vitro, which provide less information on the distribution and metabolismof drugs, and limit the interpretation and assessment of pharmacokinetics, the determination of metabolic principles, and evaluation of treatment effect. The objective of the study was to investigate the pharmacokinetic characteristics of gene recombination angiogenesis inhibitor Kringle 5 in vivo. The SPECT/CT and specific^(131)I-Kringle 5 marked by Iodogen method were both applied to explore the pharmacokinetic characteristics of^(131)I-Kringle 5 in vivo, and to investigate the dynamic distributions of^(131)I-Kringle 5 in target organs. Labeling recombinant angiogenesis inhibitor Kringle 5 using131 I with longer half-life and imaging in vivo using SPECT instead of PET,could overcome the limitations of previous methods. When the doses of^(131)I-Kringle 5 were 10.0, 7.5 and5.0 g/kg, respectively, the two-compartment open models can be determined within all the metabolic process in vivo. There were no significant differences in t1/2α, t1/2β, apparent volume of distribution and CL between those three levels. The ratio of AUC(0 1)among three different groups of 10.0, 7.5 and 5.0 g/kg was 2.56:1.44:1.0, which was close to the ratio(2:1.5:1.0). It could be clear that in the range of 5.0–10.0 g/kg, Kringle 5 was characterized by the first-order pharmacokinetics. Approximately 30 min after^(131)I-Kringle 5 was injected,^(131)I-Kringle 5 could be observed to concentrate in the heart, kidneys, liver and other organs by means of planar imaging and tomography. After 1 h of being injected, more radionuclide retained in the bladder, but not in intestinal. It could be concluded that^(131)I-Kringle 5 is mainly excreted through the kidneys. About 2 h after the injection of^(131)I-Kringle 5, the radionuclide in the heart, kidneys,liver and other organs was gradually reduced, while more radionuclide was concentrated in the bladder.The radionuclide was completely metabolized within 24 h, and the distribution of radioactivity in rats was similar to normal levels. In our study, the specific marker^(131)I-Kringle 5 and SPECT/CT were successfully used to explore pharmacokinetic characteristics of Kringle 5 in rats. The study could provide a new evaluation platform of the specific, in vivo and real-time functional imaging and pharmacokinetics for the clinical application of^(131)I-Kringle 5.
基金Sponsored by the Basic Research Foundation of Beijing Institute of Technology (BIT-UBF-200506B4217)
文摘A simple, sensitive ane selective high performance liquid chromatographic (HPLC) method with UV detection (320 nm) was developed and validated for determination of mangiferin in rat plasma and tissues. Mangiferin and internal standard (spinosin) were separated using mobile phase of acetonitrile-water (20:80, v/v) with 1% glacial acetic acid and 1% THF on a Phenomenex gemini C18 column. The flow rate was 0.7 mL/min. The calibration curves of mangiferin in plasma and tissues were linear over the investigated ranges. The intra- and inter-run preeisions for all samples were less than 13.8 %. The time-concentration curve of mangiferin after intravenous administration to rats corresponded to two-compartment model. The main pharmacokinetic parameters T0.5α, T0.5β, CL and AUC0-T were 15.87 min, 26.15 rain, 6.1 L/(min·kg) and 3.28 mg· min/mL, respectively. The highest and lowest levels of mangiferin occurred in spleen and brain, respectively. Mangiferin was not found in liver. After intravenous administration, the drug was distributed extensively and transferred quickly in rats in vivo.
基金financially supported by the National Natural Science Foundation of China (No. 81560721)。
文摘Alpinia officinarum Hance of the Chinese traditional herb for the treatment of emesis, abdominal pain and diarrhea has been used to counteract gastric disease induced by indomethacin in rats without obvious side effects. However, the role of herb-drug interaction between indomethacin and A. officinarum based on pharmacokinetic, tissue distribution and excretion still remains unknown. In this study, an ultra-fast liquid-tandem mass spectrometry(UFLC-MS/MS) method was developed for simultaneous determination of indomethacin and its three metabolites, O-desmethylindomethacin(ODI), deschlorobenzoylindomethacin(NDI) and indomethacin acyl-b-D-glucuronide(IDAbG) by oral administration of indomethacin solution with and without the ethanolic extract of A. officinarum and applied to comparative pharmacokinetic, tissue distribution and excretion studies. Our results clarified that oral administration of A. officinarum produced significant alterations in the pharmacokinetic parameters of indomethacin. And the pharmacokinetic interaction between indomethacin and A. officinarum reduced the systemic exposure of indomethacin and increased its elimination. Tissue distribution results demonstrated that co-administration of A. Officinarum could not reduce the accumulation of indomethacin in the target tissue of the stomach, but could accelerate the excretions of indomethacin and its three metabolites including ODI, NDI and IDAb G in the bile and feces of rats in the excretion study.Therefore, A. Officinarum might have a gastrointestinal protective effect through the interaction role with indomethacin based on the pharmacokinetics and excretion in rats.
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This study was financially supported by the National Natural Science Foundation of the People's Republic of China(Grant Nos.:81773814 and 81530098)the National Key Special Project of Science and Technology for Innovation Drugs of China(Project No.:2017ZX09301013)the National Key Research and Development Program(Grant No.:2018YFC0807403).
文摘Cystine is the primary source material for the synthesis of glutathione.However,the pharmacokinetics and tissue distribution of cystine are largely unknown.A surrogate analyte D_(4)-cystine was employed to generate calibration curves for the determination of levels of D_(4)-cystine and endogenous cystine in mice by liquid chromatography-tandem mass spectrometry(LC-MS/MS).Validation assessments proved the sensitivity,specificity and reproducibility of the method with a lower limit of quantification(LLOQ)of 5 ng/mL over 5e5000 ng/mL in plasma.The pharmacokinetics of D_(4)-cystine were evaluated after administering injections and oral solutions,both of which minimally impacted endogenous cystine levels.The absolute bioavailability of cystine was 18.6%,15.1%and 25.6%at doses of 25,50 and 100 mg/kg,respectively.Intravenously injected D_(4)-cystine resulted in dramatically high plasma levels with reduced levels in the brain and liver.Intragastrically administered D_(4)-cystine resulted in high levels in the plasma and stomach with relatively low levels in the lung,kidney,heart and brain.
基金Supported by Scientific and Technological Planning Project of Yunnan Province(2013FB118)Innovation Team Project of Kunming Medical University(CXTD201604)Scientific Research Foundation of Yunnan Provincial Department of Education(2017zDX161)
文摘[Objectives]To establish an acute yunaconitine poisoning rat model with a single oral administration and to determine the contents of yunaconitine in rat tissues by UPLC-MS/MS method,then investigate the distribution of yunaconitine in rats. [Methods]The rats were randomly divided into three groups and were intragastrically administered a single dose of 2. 2,1. 1,and 0. 7 mg/kg of yunaconitine,respectively.The rats were killed 2 h later,the stomach tissue,intestine tissue,liver tissue,pancreas tissue,kidney tissue,lung tissue,spleen tissue,heart tissue,bladder tissue,testis tissue,brain tissue and heart blood samples were collected. The contents of yunaconitine in the biological materials were determined by UPLC-MS/MS method after the biological samples extracted by liquid-liquid extraction. [Results] A rat model of the yunaconitine poisoning was made with a single dose of 1. 1 mg/kg,the concentrations of yunaconitine shown in the organs with the following order: stomach,small intestine,liver,pancreas,kidney,lung,spleen,heart,bladder,testis,heart blood and brain. [Conclusions]Yunaconitine was widely distributed in rats,especially the levels in the stomach,small intestine and liver were the highest. The conclusion is expected to provide a basis for the selection of test materials for the poisoning of Aconitum vilmorinianum Kom.
基金supported by CAMS Innovation Fund for Medical Sciences(Grant No.:2019-I2M-5e020)the National Natural Science Foundation of China(Grant No.:81503154)the National Major Scientific and Technological Special Project for Significant New Drugs Development(Grant No.:2017ZX09101002-001-005).
文摘Rotundic acid(RA),an ursane-type pentacyclic triterpene acid isolated from the dried barks of Ilex rotunda Thunb.(Aquifoliaceae),possesses diverse bioactivities.To further study its pharmacokinetics,a simple and sensitive liquid chromatography with triple quadrupole mass spectrometry(LC-QqQ-MS/MS)method was developed and validated to quantify RA concentration in rat plasma and tissue using etofesalamide as an internal standard(IS).Plasma and tissue samples were subjected to one-step protein precipitation.Chromatographic separation was achieved on a ZORBAX Eclipse XDB-C_(18) column(4.6mm×50mm,5μm)under gradient conditions with eluents of methanol:acetonitrile(1:1,V/V)and 5mM ammonium formate:methanol(9:1,V/V)at 0.5mL/min.Multiple reaction monitoring transitions were performed at m/z 487.30→437.30 for RA and m/z 256.10→227.10 for IS in the negative mode.The developed LC-QqQ-MS/MS method exhibited good linearity(2-500 ng/mL)and was fully validated in accordance with U.S.Food and Drug Administration bioanalytical guidelines.Dose proportionality and bioavailability in rats were determined by comparing pharmacokinetic data after single oral(10,20,and 40mg/kg)and intravenous(10mg/kg)administration of RA.Tissue distribution was studied following oral administration at 20mg/kg.The results showed that the absolute bioavailability of RA after administration at different doses ranged from 16.1%to 19.4%.RA showed good dose proportionality over a dose range of 10-40 mg/kg.RA was rapidly absorbed in a dose-dependent manner and highly distributed in the liver.In conclusion,this study is the first to systematically elucidate the absorption and distribution characteristics of RA in rats,which can provide additional information for further development and evaluation of RA in drug metabolism and pharmacokinetic studies.
文摘Background: The aim of this study was to investigate the distribution of the c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles in the major organs of mice by MR imaging. Methods: Sixty BALB/c mice were randomly divided into experimental and control groups. MR scans were performed in each mouse of the experimental group at five different time points (10, 30, 60, 180 and 360 min) after injection of the antisense probe. The signal from each major organ (liver, spleen, heart, kidney and muscle tissue) in comparison with the background signal (signal to noise ratio) was determined at each time point as a measure of the distribution of the antisense probe. Six control mice were killed at each of the same time points and the organs immediately removed for determination of their iron content. Results: After injection of the antisense probe, the highest enrichment of the probe was seen in the spleen, reaching a peak at 180 min, followed by the liver, muscle, heart and kidney. Conclusions: MR imaging can visualize the distribution of c-erbB2 antisense probe labeled with superparamagnetic iron oxide nanoparticles in the major organs of mice, and this may provide the basis for further in vivo studies of MR imaging time and dose selection.