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
Vegetable fields are often contaminated by heavy metals,and Spodoptera exigua is a major vegetable pest which is stressed by heavy metals mainly by feeding.In this study,cadmium accumulation in the tissues of S.exigua...Vegetable fields are often contaminated by heavy metals,and Spodoptera exigua is a major vegetable pest which is stressed by heavy metals mainly by feeding.In this study,cadmium accumulation in the tissues of S.exigua exposed to cadmium and its effects on the growth and development of the parents and the offspring were investigated.Under the stress of different concentrations of cadmium(0.2,3.2,and 51.2 mg kg^(-1)),the cadmium content in each tissue of S.exigua increased in a dose-dependent manner.At the larval stage,the highest cadmium accumulation was found in midgut in all three cadmium treatments,but at the adult stage,the highest cadmium content was found in fat body.In addition,the cadmium content in ovaries was much higher than in testes.When F1S.exigua was stressed by cadmium and the F_(2)generation was not fed a cadmium-containing diet,the larval survival,pupation rate,emergence rate and fecundity of the F_(2)generation were significantly reduced in the 51.2 mg kg^(-1)treatment compared to the corresponding F1generation.Even in the F_(2)generation of the 3.2 mg kg^(-1)treatment,the fecundity was significantly lower than in the parental generation.The fecundity of the only-female stressed treatment was significantly lower than that of the only-male stressed treatment at the 3.2 and 51.2 mg kg^(-1)cadmium exposure levels.When only mothers were stressed at the larval stage,the fecundity of the F_(2)generation was significantly lower than that of the F1generation in the 51.2 mg kg^(-1)treatment,and it was also significantly lower than in the 3.2 and 0.2 mg kg^(-1)treatments.The results of our study can provide useful information for forecasting the population increase trends under different heavy metal stress conditions and for the reliable environmental risk assessment of heavy metal pollution.展开更多
An HPLC method for the determination of isovitexin in rat plasma and different tissues was developed.The separation was achieved on a C_（18）column with a mobile phase consisting of methanol-1% acetum（40：60,v/v）at...An HPLC method for the determination of isovitexin in rat plasma and different tissues was developed.The separation was achieved on a C_（18）column with a mobile phase consisting of methanol-1% acetum（40：60,v/v）at a detection wavelength of 338 nm and a column temperature of 30℃.Rutin was chosen as the internal standard.The linear range of the standard curves was 0.20-128.75μg/mL in the plasma and 0.024-3.09μg/mL in the tissues.The LOQ was 0.19μg/mL in the plasma and 0.024μg/mL in the tissues.The relative recoveries of isovitexin ranged from 93% to 105% in the plasma and 87% to 112% in the tissues.The intra-and inter-day precisions were all below 8%.The pharmacokinetics and tissue distribution of isovitexin in rats were studied with the method.Blood samples were collected at fixed time intervals after the i.v.injection of isovitexin at a dosage of 18.75,3.75 and 0.75 mg/kg;the tissue samples（brain,liver,kidney,heart,lung,spleen and ovary）were obtained at 10,30,and 60 min after the i.v.injection of isovitexin at a dosage of 18.75 mg/kg.The pharmacokinetics of the isovitexin in three different dosages in the rats fit the two-compartment open model.The isovitexin displayed linear dynamics in the dosage range of 0.75-18.75 mg/kg.The mean value of t_（1/2α）was 1.54-1.84 min,and t_（1/2β）was 36.94-46.27 min at the three dosages.The tissue distribution study showed that the sequence of tissue drug concentration from high to low was kidneyliverlung≈ovaryheart≈spleenbrain.展开更多
Liposomes are used as carriers for targeted drug delivery by the intravenous route. The aim of our study was to prepare lomustine loaded liposomes （CCNU-Lips） and evaluate its physicochemical properties and the tiss...Liposomes are used as carriers for targeted drug delivery by the intravenous route. The aim of our study was to prepare lomustine loaded liposomes （CCNU-Lips） and evaluate its physicochemical properties and the tissue targeting after intravenous （i.v.） injection. CCNU-Lips were prepared by film dispersion method. In vitro drug release was investigated in phosphate-buffered saline （pH 6.8） at 37℃. The concentrations of CCNU in selected organs were determined using reversed-phase high-performance liquid chromatography （HPLC） following i.v. administration of CCNU-Lips and inclusion complex solution of CCNU with hydroxypropyl-β-cyclodextrin （CCNU-Sol）. CCNU-Lips had an average diameter of （189.8±28.5） nm with a zeta potential of （-19.13±0.12） mV and the in vitro drug release was monitored for up to 3 d, and the release behavior was in accordance with Weibull-equation. The CCNU-Lips exhibited a longer elimination half life （t1/2β） in vivo compared with CCNU-Sol after i.v. injection to New Zealand rabbits. The encapsulation of lomustine in liposomes also changed its biodistribution in mice. CCNU-Lips showed significant brain targeting with AUC, Te and Re of the brain all showing obvious elevation. These results indicated that CCNU-Lips were promising passive targeting formulation to the brain.展开更多
The present study aimed at studying the characteristics of tissue distribution and excretion of scopoletin,a coumarin compound,in Sprague-Dawley rats.Scopoletin was orally administered at a dose of 50 mg/kg,and the co...The present study aimed at studying the characteristics of tissue distribution and excretion of scopoletin,a coumarin compound,in Sprague-Dawley rats.Scopoletin was orally administered at a dose of 50 mg/kg,and the concentrations in heart,liver,spleen,lung,kidney,muscle,fat,brain,testis,uterus,stomach and small intestine were determined at 5,15,30,60,120,240 min post-dose,respectively.It was shown that scopoletin was widely distributed into various tissues and reached the maximal concentrations in most tissues at 15 min post-dose,and the levels in liver,kidney,stomach and small intestine were relatively higher.Furthermore,the excretions of scopoletin in bile,urine and feces were only 0.032%,3.752% and 0.784%,respectively,suggesting that scopoletin was mainly eliminated by metabolism rather than excretion as parent drug.展开更多
A novel organoselenium compound,WB（1,2-[bis（1,2-benzisoselenazolone-3（2H）-ketone）]pentane） has indicated anti-tumor activity.Its pharmacokinetic data has never been determined.By using the H22 tumor bearing mous...A novel organoselenium compound,WB（1,2-[bis（1,2-benzisoselenazolone-3（2H）-ketone）]pentane） has indicated anti-tumor activity.Its pharmacokinetic data has never been determined.By using the H22 tumor bearing mouse model,the tissue distribution of WB after single and four consecutive doses（both were 120 mg/kg/d） was explored.The selenium content of the tissues was used as an indicator of WB absorption,distribution and metabolism.The selenium in the heart,liver, spleen,kidneys,lungs,stomach,pancreas,brain,colon,intestine,testes,plasma,and tumor were determined by generation atomic fluorescence spectrometry（AFS）.With single or multiple oral administration of WB,the selenium content significantly increased in the liver,stomach,colon,and intestine.The selenium content in the spleen,lungs,pancreas,testes,plasma and tumor also increased compared with the controls;but no significant changes were found in the brain and kidney.WB and its metabolites distributed predominantly in the colon,liver,stomach and intestine,which resulted in a significant increase in the selenium content in both groups.There was no observed significant accumulation of WB in the vital organs.展开更多
Dahuang-Gancao decoction(DGD)is a classical formula,which is commonly used for reliving constipation in Chinese clinic.The aim of this study was to investigate the pharmacodynamic,pharmacokinetic and tissue distributi...Dahuang-Gancao decoction(DGD)is a classical formula,which is commonly used for reliving constipation in Chinese clinic.The aim of this study was to investigate the pharmacodynamic,pharmacokinetic and tissue distribution alternations of DGD in normal and constipation mice.DGD exhibited stronger purgative effect in constipation mice by the increased fecal excretion and reduced first defection time compared with normal mice.The Cmax,AUC0-t and MRT0-t of rhein,aloe-emodin,rhein-8-O-β-D-glucoside,sennoside A,and glycyrrhizic acid as main bio-active components in DGD were markedly increased in constipation mice.The tissue distribution of the analytes in constipation mice were higher than those in normal mice with rhein>rhein-8-O-β-D-glucoside>aloe-emodin>glycyrrhizic acid>emodin in liver,and glycyrrhizic acid>rhein-8-O-β-D-glucoside>liquitin>sennoside A>rhein>aloe-emodin>emodin in colon.The kidney concentrations of the analytes showed a descending order of rhein>rhein-8-O-β-D-glucoside>sennoside A>glycyrrhizic acid>aloe-emodin>emodin,most of them were higher while rhein was lower in constipation mice than normal mice.The higher exposure of the anthraquinones in plasma,liver and colon may result in the stronger purgative effect in the constipation mice than normal mice.Rhein is mainly excreted through the kidney,the decreased level of rhein in constipation mice may explain the alleviated side effects.Accumulation of glycyrrhizic acid in colon may related with the moderate property of licorice.These results provided the experimental basis for understanding the therapeutic effects and metabolite profile of DGD.展开更多
Docetaxel (DTX), as a member of taxoid family, has been widely used in the treatment of cancers. The present study prepared pH-sensitive DTX-loaded liposomes (DTX-Lips) by thin-film dispersion method and various physi...Docetaxel (DTX), as a member of taxoid family, has been widely used in the treatment of cancers. The present study prepared pH-sensitive DTX-loaded liposomes (DTX-Lips) by thin-film dispersion method and various physico-chemical and morphological properties were examined. The pH sensitivity of in vitro DTX release and the in vivo pharmacokinetics and tissue distribution using Kunming mice were also investigated. The mean particle size and zetapotential of DTX liposomes were (277±2) nm and (-32.60±0.26) mV, respectively. Additionally, in vitro drug release study showed that the cumulative release rate was 1.3 times more at pH 5.0 than at pH 7.4, suggesting a pH-dependent releaseability of DTX-Lips. Pharmacokinetic and pharmaceutical studies in comparison with Duopafei showed that the half-timeperiod (t1/2) and area under the curve (AUC) of DTX-Lips in mouse plasma were 1.8 times longer and 2.6 times higher,respectively, and that DTX-Lips selectively accumulated in macrophage-rich organs such as liver and spleen. The seresults together suggest that the DTX-Lips could be a promising formulation for the clinical administration of DTX.展开更多
As an important bis-benzylisoquinoline alkaloid isolated from the bulbous root ofStephania tetrandra S. Moore, tetrandrine （Tet） is widely used for the treatment of malignant tumor due to its properties of reversing...As an important bis-benzylisoquinoline alkaloid isolated from the bulbous root ofStephania tetrandra S. Moore, tetrandrine （Tet） is widely used for the treatment of malignant tumor due to its properties of reversing the multidrug resistance and apoptosis induction. In the present study, we aimed to evaluate the pharmacokinetics, tissue distribution and excretion of Tet in rats. Drug concentration in plasma and tissues was measured by high performance liquid chromatography （HPLC）, and the experimental data were analyzed using pharmacokinetic software DAS 2.0. The results showed that the plasma protein binding rate of Tet was 68.7%, indicating a higher protein binding drug. Tissue distribution was found in a descending order as follows： lung〉heart〉liver〉kidney〉spleen. Renal excretion was a major route of excretion, and the urine, bile and fecal excretion accounted for 25.73% of the administered dose. A UC0-∞ of Tet in the liver was 20 times greater than that in plasma, indicating that Tet had a higher affinity for the liver. Moreover, CL in the liver was the lowest among all tissues, indicating that Tet with slow elimination might result in the accumulation. Therefore, we need to adjust the dose for patients who have dysfunction in liver and kidney. In addition, therapeutic drug monitoring in long-term clinical treatment, if necessary, should be carried out.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
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
This study examined concentrations of 15 perfluoroalkyl acids（PFAAs） in tissues from male Mozambique tilapia（Oreochromis mossambicus） collected at Loskop Dam, Mpumalanga,South Africa in 2014 and 2016. Nine of the ...This study examined concentrations of 15 perfluoroalkyl acids（PFAAs） in tissues from male Mozambique tilapia（Oreochromis mossambicus） collected at Loskop Dam, Mpumalanga,South Africa in 2014 and 2016. Nine of the 15 PFAAs were detected frequently and were included in statistical analysis and included two of the most commonly known PFAAs,perfluorooctanesulfonic acid（PFOS）（median, 41.6 ng/g） and perfluorooctanoic acid（PFOA）（median, 0.0825 ng/g）. Of the tissues measured, plasma（2016 and 2014 median, 22.2 ng/g）contained the highest PFAA burden followed by（in descending order）： liver（median,11.6 ng/g）, kidney（median, 9.04 ng/g）, spleen（median, 5.92 ng/g）, adipose（median, 2.54 ng/g）, and muscle（median, 1.11 ng/g）. Loskop Dam tilapia have been affected by an inflammatory disease of the adipose tissue known as pansteatitis, so this study also aimed to investigate relationships between PFAA tissue concentrations and incidence of pansteatitis or fish health status. Results revealed that healthy tilapia exhibited an overall higher（p-value 〈 0.05） PFAA burden than pansteatitis-affected tilapia across all tissues.Further analysis showed that organs previously noted in the literature to contain the highest PFAA concentrations, such as kidney, liver, and plasma, were the organs driving the difference in PFAA burden between the two tilapia groups. Care must be taken in the interpretations we draw from not only the results of our study, but also other PFAA measurements made on populations（human and wildlife alike） under differing health status.展开更多
This study was conducted in adult male Sprague -- Dawley rats to determine the distribution of [3H]-nicotine in blood and tissues following a bolus injection and a constant infusion of pure nicotine. The animals were ...This study was conducted in adult male Sprague -- Dawley rats to determine the distribution of [3H]-nicotine in blood and tissues following a bolus injection and a constant infusion of pure nicotine. The animals were anesthetized and injected with either 0.5 ml of nicotine solution or given a constant infusion of the same nicotine solution with identical amounts of radioactive nicotine. After sacrifice, blood, brain, trachea, salivery gland, esophagus, lung, heart, liver, fundus, antrum, spleen, pancreas, duodenum, jejunum, ileum, cecum, colon, kidneys, adrenal gland, and testes were collected and measured for radioactivity by scintillation counting. The distribution of nicotine was found highest in kidneys by both routes of administration. Higher accumulations were also found in salivary and adrenal glands, fundus, antrum, duodenum, jejunum, ileum and colon. Retention of nicotine via constant infusion was significantly higher in esophagus, fundus antrum, spleen, cecum, pancreas, testes, heart and muscle when compared with bolus injection. Six-fold increase in retention of blood levels of nicotine were found with constant infusion. (P<0.05). The results indicate that longer retention of nicotine occurs in blood and other specific tissues such as esophagus, fundus, antrum, spleen, cecum, pancreas, testes, heart and muscle via constant exposure. These data may implicate the predisposition of these tissues to pathologic manifestations.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
To date, in vivo investigations of polysaccharide’s pharmacokinetics are significantly restricted by the difficulty in their detection. This study was conducted to establish the quantitative determination of Lycium b...To date, in vivo investigations of polysaccharide’s pharmacokinetics are significantly restricted by the difficulty in their detection. This study was conducted to establish the quantitative determination of Lycium barbarum polysaccharides(LBPs) based on fluorescein isothiocyanate(FITC) pre-labeling and to investigate their tissue distribution in rat. We obtained the calibration curves linear over the range of 0.0–25 μg/m L in rat tissue samples with correlation coefficients greater than 0.99. The inter-day and intra-day precisions(RSD, %) were within 15%, and the relative recovery ranged 95.2%–102.4%, with RSD range 1.48%–9.58%, indicating that this experiment was suitable for the determination of LBPs. The fluorescence intensity was measured after 24 h storage at room temperature, 3 times of freeze-cycle and cryopreservation at –20 ℃ for 15 day, these results indicated that the stability of the samples was good. LBP-FITC was mainly absorbed by the small intestine and stomach, and mainly excreted in the urine through the kidney;this distinct difference in the tissue distribution of LBPs could be attributed to the size of these LBPs in relation to the pore sizes of the vascular beds in the kidney and liver. Results showed in this study enable us to comprehensively understand the biological effects of LBPs following its oral ingestion.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
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
Contamination of deoxynivalenol（DON） in grains is common worldwide and pigs are particularly susceptible to this mycotoxin. The distribution of DON in porcine tissues following intravenous administration was investi...Contamination of deoxynivalenol（DON） in grains is common worldwide and pigs are particularly susceptible to this mycotoxin. The distribution of DON in porcine tissues following intravenous administration was investigated in this study. Fifteen pigs were randomly divided into three groups. Animals in groups A and B were administrated with DON at the dose of 250 and 750 μg kg–1 body weight, respectively, while group C served as blank control. Plasma, bile and 27 tissues were collected at 30 min post-administration. DON concentrations in all samples were tested using high-performance liquid chromatography-tandem mass spectrometry（HPLC-MS/MS）. To observe the distribution of DON in tissues, these samples were further subjected to the immunohistochemical analyses. Totally, the bile and 13 tissues were sampled for DON-based detection, including kidney, mesenteric lymph nodes, muscle, stomach, jejunum, colon, plasma, spleen, rectum, cecum, liver, ileum, and duodenum. No significant difference was observed for the concentrations of DON in duodenum, ileum and liver samples between groups A and B; while the DON concentrations in cecum and rectum of group B were significantly higher（P-value 〈0.05） than those in group A. In addition, the DON concentrations in stomach, jejunum, colon, mesenteric lymph nodes, muscle, kidney, spleen, bile, and plasma of group B were remarkably higher than those of group A（P-value〈0.01）. Levels of DON in other 14 tissues including medulla oblongata, midbrain, diencephalon, pons, tip and tongue body, tongue, soft palate, tonsils, pharyngeal mucosa, oral buccal mucosa, thymus, thyroid, esophagus and adrenal gland were all below the limit of detection. The results of immunohistochemistry showed that 11 tissue samples（medullaoblongata, tonsil, adrenal medulla, thyroid gland, thyroid, stomach, duodenum, jejunum, kidney, spleen, and mesenteric lymph nodes） were positive and DON was mainly distributed around blood vessels in these tissues. Therefore, we believed that concentrations of DON in tissues differ when pigs are in exposure to various dosages and DON causes lesions in many pig tissues.展开更多
Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest.We assess the pharma-cokinetic a...Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest.We assess the pharma-cokinetic and tissue distribution profile of imatinib in a liposome formulation.Its single dose(6.25 mg·kg-1) in a liposome formulation was administered iv to male mice.Imatinib concentration was measured in plasma,spleen,liver,kidney and brain using a HPLC assay.Non-compartmental pharmacokinetic approach was used to assess the disposition parameters.The plasma disposition profile was biphasic with a plateau-like second phase.The AUC0→∞ was 11.24 μg·h·mL-1,the elimination rate constant(kel) was 0.348 h-1 and the elimination half life(t1/2) was 2.0 h.The mean residence time(MRT) was 2.59 h,VSS was 1.44 L·kg-1 and clearance was 0.56 L·h·kg-1.Liver achieved the highest tissue exposure:CMAX = 18.72 μg·mL-1;AUC0→∞ = 58.18 μg·h·mL-1 and longest t1/2(4.29 h) and MRT(5.31 h).Kidney and spleen AUC0→∞ were 47.98 μg·h·mL-1 and 23.46 μg·h·mL-1,respectively.Half-life was 1.83 h for the kidney and 3.37 h for the spleen.Imatinib penetrated into the brain reaching ～1 μg·g-1.Upon correction by organ blood flow the spleen showed the largest uptake efficiency.Liposomal imatinib presented extensive biodistribution.The drug uptake kinetics showed mechanism differences amongst the tissues.These findings encourage the development of novel imatinib formulations to treat other cancers.展开更多
To investigate the disposition and tissue distribution of ML12 after intravenous （iv） administration in rats, the compound in plasma or in tissue was extracted into ethyl acetate under basic condition and was determ...To investigate the disposition and tissue distribution of ML12 after intravenous （iv） administration in rats, the compound in plasma or in tissue was extracted into ethyl acetate under basic condition and was determined by HPLC after extracted by dilute sulfuric acid. Excitation wavelength and emission wavelength of fluorescence detection were 278 nm and 307 nm, respectively. The data were processed with the software 3P97 to calculate the main pharmaceutical parameters of ML12. At dose of 5 and 10 mg/kg, the elimination of the drug from plasma was found to be kinetically linear, but when the dosage was 20 mg/kg, a non-linear feature was observed. The highest level of ML12 was found in the kidney. Distribution of ML12 after iv administration was extensive and the concentration-time profile was found to be fitted to an open two-compartment model.展开更多
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partially supported by the Open Project Program from the Key Laboratory of South Subtropical Fruit Biology and Genetic Resource Utilization(Ministry of Agriculture and Rural Affairs),China(212103)。
文摘Vegetable fields are often contaminated by heavy metals,and Spodoptera exigua is a major vegetable pest which is stressed by heavy metals mainly by feeding.In this study,cadmium accumulation in the tissues of S.exigua exposed to cadmium and its effects on the growth and development of the parents and the offspring were investigated.Under the stress of different concentrations of cadmium(0.2,3.2,and 51.2 mg kg^(-1)),the cadmium content in each tissue of S.exigua increased in a dose-dependent manner.At the larval stage,the highest cadmium accumulation was found in midgut in all three cadmium treatments,but at the adult stage,the highest cadmium content was found in fat body.In addition,the cadmium content in ovaries was much higher than in testes.When F1S.exigua was stressed by cadmium and the F_(2)generation was not fed a cadmium-containing diet,the larval survival,pupation rate,emergence rate and fecundity of the F_(2)generation were significantly reduced in the 51.2 mg kg^(-1)treatment compared to the corresponding F1generation.Even in the F_(2)generation of the 3.2 mg kg^(-1)treatment,the fecundity was significantly lower than in the parental generation.The fecundity of the only-female stressed treatment was significantly lower than that of the only-male stressed treatment at the 3.2 and 51.2 mg kg^(-1)cadmium exposure levels.When only mothers were stressed at the larval stage,the fecundity of the F_(2)generation was significantly lower than that of the F1generation in the 51.2 mg kg^(-1)treatment,and it was also significantly lower than in the 3.2 and 0.2 mg kg^(-1)treatments.The results of our study can provide useful information for forecasting the population increase trends under different heavy metal stress conditions and for the reliable environmental risk assessment of heavy metal pollution.
基金Foundation for Distinguished Young Talents in Higher Education of Guangdong and Foundation for Young Scholars of Guangdong Medical College(Grant No XQ0802)
文摘An HPLC method for the determination of isovitexin in rat plasma and different tissues was developed.The separation was achieved on a C_（18）column with a mobile phase consisting of methanol-1% acetum（40：60,v/v）at a detection wavelength of 338 nm and a column temperature of 30℃.Rutin was chosen as the internal standard.The linear range of the standard curves was 0.20-128.75μg/mL in the plasma and 0.024-3.09μg/mL in the tissues.The LOQ was 0.19μg/mL in the plasma and 0.024μg/mL in the tissues.The relative recoveries of isovitexin ranged from 93% to 105% in the plasma and 87% to 112% in the tissues.The intra-and inter-day precisions were all below 8%.The pharmacokinetics and tissue distribution of isovitexin in rats were studied with the method.Blood samples were collected at fixed time intervals after the i.v.injection of isovitexin at a dosage of 18.75,3.75 and 0.75 mg/kg;the tissue samples（brain,liver,kidney,heart,lung,spleen and ovary）were obtained at 10,30,and 60 min after the i.v.injection of isovitexin at a dosage of 18.75 mg/kg.The pharmacokinetics of the isovitexin in three different dosages in the rats fit the two-compartment open model.The isovitexin displayed linear dynamics in the dosage range of 0.75-18.75 mg/kg.The mean value of t_（1/2α）was 1.54-1.84 min,and t_（1/2β）was 36.94-46.27 min at the three dosages.The tissue distribution study showed that the sequence of tissue drug concentration from high to low was kidneyliverlung≈ovaryheart≈spleenbrain.
文摘Liposomes are used as carriers for targeted drug delivery by the intravenous route. The aim of our study was to prepare lomustine loaded liposomes （CCNU-Lips） and evaluate its physicochemical properties and the tissue targeting after intravenous （i.v.） injection. CCNU-Lips were prepared by film dispersion method. In vitro drug release was investigated in phosphate-buffered saline （pH 6.8） at 37℃. The concentrations of CCNU in selected organs were determined using reversed-phase high-performance liquid chromatography （HPLC） following i.v. administration of CCNU-Lips and inclusion complex solution of CCNU with hydroxypropyl-β-cyclodextrin （CCNU-Sol）. CCNU-Lips had an average diameter of （189.8±28.5） nm with a zeta potential of （-19.13±0.12） mV and the in vitro drug release was monitored for up to 3 d, and the release behavior was in accordance with Weibull-equation. The CCNU-Lips exhibited a longer elimination half life （t1/2β） in vivo compared with CCNU-Sol after i.v. injection to New Zealand rabbits. The encapsulation of lomustine in liposomes also changed its biodistribution in mice. CCNU-Lips showed significant brain targeting with AUC, Te and Re of the brain all showing obvious elevation. These results indicated that CCNU-Lips were promising passive targeting formulation to the brain.
基金The Fundamental Research Funds for the Central Universities(Grant No.JKZ2011016)the Priority Academic Program Development of Jiangsu Higher Education Institutions
文摘The present study aimed at studying the characteristics of tissue distribution and excretion of scopoletin,a coumarin compound,in Sprague-Dawley rats.Scopoletin was orally administered at a dose of 50 mg/kg,and the concentrations in heart,liver,spleen,lung,kidney,muscle,fat,brain,testis,uterus,stomach and small intestine were determined at 5,15,30,60,120,240 min post-dose,respectively.It was shown that scopoletin was widely distributed into various tissues and reached the maximal concentrations in most tissues at 15 min post-dose,and the levels in liver,kidney,stomach and small intestine were relatively higher.Furthermore,the excretions of scopoletin in bile,urine and feces were only 0.032%,3.752% and 0.784%,respectively,suggesting that scopoletin was mainly eliminated by metabolism rather than excretion as parent drug.
基金National Major Projects on Drug Research and Technology(Grant No.2009ZX09103-032)
文摘A novel organoselenium compound,WB（1,2-[bis（1,2-benzisoselenazolone-3（2H）-ketone）]pentane） has indicated anti-tumor activity.Its pharmacokinetic data has never been determined.By using the H22 tumor bearing mouse model,the tissue distribution of WB after single and four consecutive doses（both were 120 mg/kg/d） was explored.The selenium content of the tissues was used as an indicator of WB absorption,distribution and metabolism.The selenium in the heart,liver, spleen,kidneys,lungs,stomach,pancreas,brain,colon,intestine,testes,plasma,and tumor were determined by generation atomic fluorescence spectrometry（AFS）.With single or multiple oral administration of WB,the selenium content significantly increased in the liver,stomach,colon,and intestine.The selenium content in the spleen,lungs,pancreas,testes,plasma and tumor also increased compared with the controls;but no significant changes were found in the brain and kidney.WB and its metabolites distributed predominantly in the colon,liver,stomach and intestine,which resulted in a significant increase in the selenium content in both groups.There was no observed significant accumulation of WB in the vital organs.
基金supported by the National Natural Science Foundation of China(No.81603258)Youth Talent Project Funded by Shaanxi Higher Education Association for Science and Technology(No.20180307)+1 种基金Subject Innovation Team of Shaanxi University of Chinese Medicine(No.2019-YL10)Key Research and Development Program of Shaanxi(No.2019-SF-300)
文摘Dahuang-Gancao decoction(DGD)is a classical formula,which is commonly used for reliving constipation in Chinese clinic.The aim of this study was to investigate the pharmacodynamic,pharmacokinetic and tissue distribution alternations of DGD in normal and constipation mice.DGD exhibited stronger purgative effect in constipation mice by the increased fecal excretion and reduced first defection time compared with normal mice.The Cmax,AUC0-t and MRT0-t of rhein,aloe-emodin,rhein-8-O-β-D-glucoside,sennoside A,and glycyrrhizic acid as main bio-active components in DGD were markedly increased in constipation mice.The tissue distribution of the analytes in constipation mice were higher than those in normal mice with rhein>rhein-8-O-β-D-glucoside>aloe-emodin>glycyrrhizic acid>emodin in liver,and glycyrrhizic acid>rhein-8-O-β-D-glucoside>liquitin>sennoside A>rhein>aloe-emodin>emodin in colon.The kidney concentrations of the analytes showed a descending order of rhein>rhein-8-O-β-D-glucoside>sennoside A>glycyrrhizic acid>aloe-emodin>emodin,most of them were higher while rhein was lower in constipation mice than normal mice.The higher exposure of the anthraquinones in plasma,liver and colon may result in the stronger purgative effect in the constipation mice than normal mice.Rhein is mainly excreted through the kidney,the decreased level of rhein in constipation mice may explain the alleviated side effects.Accumulation of glycyrrhizic acid in colon may related with the moderate property of licorice.These results provided the experimental basis for understanding the therapeutic effects and metabolite profile of DGD.
基金Project supported by the Independent Innovation Foundation of Shandong University, China (No. 2010TS041)the Shandong Provincial Special Funds for Postdoctoral Innovative Projects, China(No. 201003069)
文摘Docetaxel (DTX), as a member of taxoid family, has been widely used in the treatment of cancers. The present study prepared pH-sensitive DTX-loaded liposomes (DTX-Lips) by thin-film dispersion method and various physico-chemical and morphological properties were examined. The pH sensitivity of in vitro DTX release and the in vivo pharmacokinetics and tissue distribution using Kunming mice were also investigated. The mean particle size and zetapotential of DTX liposomes were (277±2) nm and (-32.60±0.26) mV, respectively. Additionally, in vitro drug release study showed that the cumulative release rate was 1.3 times more at pH 5.0 than at pH 7.4, suggesting a pH-dependent releaseability of DTX-Lips. Pharmacokinetic and pharmaceutical studies in comparison with Duopafei showed that the half-timeperiod (t1/2) and area under the curve (AUC) of DTX-Lips in mouse plasma were 1.8 times longer and 2.6 times higher,respectively, and that DTX-Lips selectively accumulated in macrophage-rich organs such as liver and spleen. The seresults together suggest that the DTX-Lips could be a promising formulation for the clinical administration of DTX.
基金The Scientific Research Fund Project of Heilongjiang University of Chinese Medicine(Grant No.201408)
文摘As an important bis-benzylisoquinoline alkaloid isolated from the bulbous root ofStephania tetrandra S. Moore, tetrandrine （Tet） is widely used for the treatment of malignant tumor due to its properties of reversing the multidrug resistance and apoptosis induction. In the present study, we aimed to evaluate the pharmacokinetics, tissue distribution and excretion of Tet in rats. Drug concentration in plasma and tissues was measured by high performance liquid chromatography （HPLC）, and the experimental data were analyzed using pharmacokinetic software DAS 2.0. The results showed that the plasma protein binding rate of Tet was 68.7%, indicating a higher protein binding drug. Tissue distribution was found in a descending order as follows： lung〉heart〉liver〉kidney〉spleen. Renal excretion was a major route of excretion, and the urine, bile and fecal excretion accounted for 25.73% of the administered dose. A UC0-∞ of Tet in the liver was 20 times greater than that in plasma, indicating that Tet had a higher affinity for the liver. Moreover, CL in the liver was the lowest among all tissues, indicating that Tet with slow elimination might result in the accumulation. Therefore, we need to adjust the dose for patients who have dysfunction in liver and kidney. In addition, therapeutic drug monitoring in long-term clinical treatment, if necessary, should be carried out.
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 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.
基金supported by the Medical University of South Carolina Center for Global Healthsupported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (Grant No 101054)
文摘This study examined concentrations of 15 perfluoroalkyl acids（PFAAs） in tissues from male Mozambique tilapia（Oreochromis mossambicus） collected at Loskop Dam, Mpumalanga,South Africa in 2014 and 2016. Nine of the 15 PFAAs were detected frequently and were included in statistical analysis and included two of the most commonly known PFAAs,perfluorooctanesulfonic acid（PFOS）（median, 41.6 ng/g） and perfluorooctanoic acid（PFOA）（median, 0.0825 ng/g）. Of the tissues measured, plasma（2016 and 2014 median, 22.2 ng/g）contained the highest PFAA burden followed by（in descending order）： liver（median,11.6 ng/g）, kidney（median, 9.04 ng/g）, spleen（median, 5.92 ng/g）, adipose（median, 2.54 ng/g）, and muscle（median, 1.11 ng/g）. Loskop Dam tilapia have been affected by an inflammatory disease of the adipose tissue known as pansteatitis, so this study also aimed to investigate relationships between PFAA tissue concentrations and incidence of pansteatitis or fish health status. Results revealed that healthy tilapia exhibited an overall higher（p-value 〈 0.05） PFAA burden than pansteatitis-affected tilapia across all tissues.Further analysis showed that organs previously noted in the literature to contain the highest PFAA concentrations, such as kidney, liver, and plasma, were the organs driving the difference in PFAA burden between the two tilapia groups. Care must be taken in the interpretations we draw from not only the results of our study, but also other PFAA measurements made on populations（human and wildlife alike） under differing health status.
文摘This study was conducted in adult male Sprague -- Dawley rats to determine the distribution of [3H]-nicotine in blood and tissues following a bolus injection and a constant infusion of pure nicotine. The animals were anesthetized and injected with either 0.5 ml of nicotine solution or given a constant infusion of the same nicotine solution with identical amounts of radioactive nicotine. After sacrifice, blood, brain, trachea, salivery gland, esophagus, lung, heart, liver, fundus, antrum, spleen, pancreas, duodenum, jejunum, ileum, cecum, colon, kidneys, adrenal gland, and testes were collected and measured for radioactivity by scintillation counting. The distribution of nicotine was found highest in kidneys by both routes of administration. Higher accumulations were also found in salivary and adrenal glands, fundus, antrum, duodenum, jejunum, ileum and colon. Retention of nicotine via constant infusion was significantly higher in esophagus, fundus antrum, spleen, cecum, pancreas, testes, heart and muscle when compared with bolus injection. Six-fold increase in retention of blood levels of nicotine were found with constant infusion. (P<0.05). The results indicate that longer retention of nicotine occurs in blood and other specific tissues such as esophagus, fundus, antrum, spleen, cecum, pancreas, testes, heart and muscle via constant exposure. These data may implicate the predisposition of these tissues to pathologic manifestations.
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.
基金the support from the National Key Research and Development Program of China(No.2016YFD400604-02)the National Natural Science Foundation of China(No.82073551,82003457,81273069)+3 种基金the Postgraduate Research&Practice Innovation Program of Jiangsu Province(No.KYCX19_0121)the Scientific Research Foundation of Graduate School of Southeast University(No.YBPY1944)the Fundamental Research Funds for the Central Universities(No.2242020R10006)CNS Research Fund for DRI。
文摘To date, in vivo investigations of polysaccharide’s pharmacokinetics are significantly restricted by the difficulty in their detection. This study was conducted to establish the quantitative determination of Lycium barbarum polysaccharides(LBPs) based on fluorescein isothiocyanate(FITC) pre-labeling and to investigate their tissue distribution in rat. We obtained the calibration curves linear over the range of 0.0–25 μg/m L in rat tissue samples with correlation coefficients greater than 0.99. The inter-day and intra-day precisions(RSD, %) were within 15%, and the relative recovery ranged 95.2%–102.4%, with RSD range 1.48%–9.58%, indicating that this experiment was suitable for the determination of LBPs. The fluorescence intensity was measured after 24 h storage at room temperature, 3 times of freeze-cycle and cryopreservation at –20 ℃ for 15 day, these results indicated that the stability of the samples was good. LBP-FITC was mainly absorbed by the small intestine and stomach, and mainly excreted in the urine through the kidney;this distinct difference in the tissue distribution of LBPs could be attributed to the size of these LBPs in relation to the pore sizes of the vascular beds in the kidney and liver. Results showed in this study enable us to comprehensively understand the biological effects of LBPs following its oral ingestion.
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.
基金Financial support for this work was provided by the National Basic Research Program of China (2009CB118805)the Centre for Veterinary of Drug Residues, College of Veterinary Medicine, South China Agricultural University
文摘Contamination of deoxynivalenol（DON） in grains is common worldwide and pigs are particularly susceptible to this mycotoxin. The distribution of DON in porcine tissues following intravenous administration was investigated in this study. Fifteen pigs were randomly divided into three groups. Animals in groups A and B were administrated with DON at the dose of 250 and 750 μg kg–1 body weight, respectively, while group C served as blank control. Plasma, bile and 27 tissues were collected at 30 min post-administration. DON concentrations in all samples were tested using high-performance liquid chromatography-tandem mass spectrometry（HPLC-MS/MS）. To observe the distribution of DON in tissues, these samples were further subjected to the immunohistochemical analyses. Totally, the bile and 13 tissues were sampled for DON-based detection, including kidney, mesenteric lymph nodes, muscle, stomach, jejunum, colon, plasma, spleen, rectum, cecum, liver, ileum, and duodenum. No significant difference was observed for the concentrations of DON in duodenum, ileum and liver samples between groups A and B; while the DON concentrations in cecum and rectum of group B were significantly higher（P-value 〈0.05） than those in group A. In addition, the DON concentrations in stomach, jejunum, colon, mesenteric lymph nodes, muscle, kidney, spleen, bile, and plasma of group B were remarkably higher than those of group A（P-value〈0.01）. Levels of DON in other 14 tissues including medulla oblongata, midbrain, diencephalon, pons, tip and tongue body, tongue, soft palate, tonsils, pharyngeal mucosa, oral buccal mucosa, thymus, thyroid, esophagus and adrenal gland were all below the limit of detection. The results of immunohistochemistry showed that 11 tissue samples（medullaoblongata, tonsil, adrenal medulla, thyroid gland, thyroid, stomach, duodenum, jejunum, kidney, spleen, and mesenteric lymph nodes） were positive and DON was mainly distributed around blood vessels in these tissues. Therefore, we believed that concentrations of DON in tissues differ when pigs are in exposure to various dosages and DON causes lesions in many pig tissues.
基金the International Medical University(IMU)for financial support:Grant#B0104RES(05)2007.
文摘Imatinib is an efficacious anticancer drug with a spectrum of potential antitumour applications limited by poor biodistribution at therapeutic concentrations to the tissues of interest.We assess the pharma-cokinetic and tissue distribution profile of imatinib in a liposome formulation.Its single dose(6.25 mg·kg-1) in a liposome formulation was administered iv to male mice.Imatinib concentration was measured in plasma,spleen,liver,kidney and brain using a HPLC assay.Non-compartmental pharmacokinetic approach was used to assess the disposition parameters.The plasma disposition profile was biphasic with a plateau-like second phase.The AUC0→∞ was 11.24 μg·h·mL-1,the elimination rate constant(kel) was 0.348 h-1 and the elimination half life(t1/2) was 2.0 h.The mean residence time(MRT) was 2.59 h,VSS was 1.44 L·kg-1 and clearance was 0.56 L·h·kg-1.Liver achieved the highest tissue exposure:CMAX = 18.72 μg·mL-1;AUC0→∞ = 58.18 μg·h·mL-1 and longest t1/2(4.29 h) and MRT(5.31 h).Kidney and spleen AUC0→∞ were 47.98 μg·h·mL-1 and 23.46 μg·h·mL-1,respectively.Half-life was 1.83 h for the kidney and 3.37 h for the spleen.Imatinib penetrated into the brain reaching ～1 μg·g-1.Upon correction by organ blood flow the spleen showed the largest uptake efficiency.Liposomal imatinib presented extensive biodistribution.The drug uptake kinetics showed mechanism differences amongst the tissues.These findings encourage the development of novel imatinib formulations to treat other cancers.
基金a grant from Wuhan New Drug Development Program (No.20066002103)
文摘To investigate the disposition and tissue distribution of ML12 after intravenous （iv） administration in rats, the compound in plasma or in tissue was extracted into ethyl acetate under basic condition and was determined by HPLC after extracted by dilute sulfuric acid. Excitation wavelength and emission wavelength of fluorescence detection were 278 nm and 307 nm, respectively. The data were processed with the software 3P97 to calculate the main pharmaceutical parameters of ML12. At dose of 5 and 10 mg/kg, the elimination of the drug from plasma was found to be kinetically linear, but when the dosage was 20 mg/kg, a non-linear feature was observed. The highest level of ML12 was found in the kidney. Distribution of ML12 after iv administration was extensive and the concentration-time profile was found to be fitted to an open two-compartment model.
