Aim To measure the penetration of capecitabine from the plasma into tissue and to investigate the pharmacokinetics of its metabolizing into fluorouracil (5-FU) in patients with advanced breast cancer. Methods Twenty...Aim To measure the penetration of capecitabine from the plasma into tissue and to investigate the pharmacokinetics of its metabolizing into fluorouracil (5-FU) in patients with advanced breast cancer. Methods Twenty-seven patients with breast cancer received repeated doses of 1 255 mg·m^-2 of capecitabine twice daily for 7 d. Blood, tumor, and adjacent healthy tissue samples were collected. The concentrations of capecitabine and its metabolite 5-FU were determined by HPLC. The concentration-time profiles of capecitabine and 5-FU were fitted by pharmacokinetic model. The tissue distribution factors for capecitabine and 5-FU, and the AUC ratios of 5-FU to capecitabine in plasma, tumor or adjacent healthy tissue, were calculated with pharmacokinetic parameters, respectively. Results The Ka of capecitabine was 1.17 h^-1 in plasma, 0. 46 h^-1 in tumor tissue, and 0. 61 h^-1 in healthy tissue. The AUCs of capecitabine were 2. 557 1 μg·mL^-1 ·h, 1. 629 2 μg·g^-1·h and 2. 085 0 μg·g^-1· h, and T1/2 was 0. 782 3 h, 1. 528 1 h and 1. 289 6 h in plasma, tumor, and healthy tissue, respectively. The AUCs of 5-FU were 0.418 7 μg·mL^-1 h, 1.671 7 μg·g^-1·h and 1.020 8 μg·g^-1·h; the T1/2 was 0. 631 3 h ,1.204 1 h and 1.031 2 h in plasma, tumor, and healthy tissue, respectively. The tissue distribution factors of capecitabine were 0. 637 1 in tumor (AUCcap-Tumor/AUCcap-plasma) and 0. 851 4 in healthy tissue (AUCcap-HT/AUCcap-plasma . The tissue distribution factors of 5-FU were 3. 992 6 in tumor (AUC5-FU-Tumor/AUC5-FU-plasma) and 2. 438 0 in healthy tissue (AUC5-FU-HT/AUC5-FU-plasma). The AUC ratios of 5-FU to capecitabine were 0. 1637, 1. 0261, and 0. 489 5 in plasma, tumor, and healthy tissue, respectively. Conclusion The simulation curves for the disposition of capecitabine and its metabolite 5-FU in plasma and tissue basically describe the activation process of capecitabine metabolizing to 5-FU and 5-FU elimination. There are similar distributions for capecitabine in plasma, tumor, and healthy tissue. The exposure of 5-FU in tumor was found to be 3. 992 6 times greater than that in plasma and 2. 438 0 times greater than that in healthy tissue. Capecitabine may metabolize preferentially to 5- FU in tumor tissue after oral administration.展开更多
Myocyte enhancer factor 2B (MEF2B) gene belongs to myocyte enhancer factor 2 (MEF2) gene family. They are all widely expressed in muscle and nerve tissues of human and animals. MEF2B plays an important role in the...Myocyte enhancer factor 2B (MEF2B) gene belongs to myocyte enhancer factor 2 (MEF2) gene family. They are all widely expressed in muscle and nerve tissues of human and animals. MEF2B plays an important role in the growth of muscle, development and differentiation of nerve system and liver fibrosis. This re- view mainly focused on the structural characteristics, tissue distribution, biological functions and research progress of MEF2B gene in human and animals.展开更多
The purpose of this study is to characterize the tissue distribution, excretion and pharmacokinetics profiles of R-hap in healthy Wistar rats. R-hap was radiolabeled by the IODO-GEN method. Tissue distribution and uri...The purpose of this study is to characterize the tissue distribution, excretion and pharmacokinetics profiles of R-hap in healthy Wistar rats. R-hap was radiolabeled by the IODO-GEN method. Tissue distribution and urinary, fecal and biliary excretion patterns of ^125I-R-hap were investigated following a single i.v. bolus injection. Pharmacokinetics properties of ^125I-R-hap were also examined after a single i.v. bolus injection. The trichloroacetic acid (TCA) precipitated radioactivity was widely distributed and rapiclly diminished in most tissues. Kidney contained the highest radioactivity among all organs and the distribution of ^125I-R-hap to fat was minimal. The cumulative excretion of ^125I-R-hap reached 71.81% ± 2.15% of the administered radioactivity at 48 h and 94.71% ± 1.50% at 120 h. Urinary excretion was the dominant route of elimination following i.v. administration, as 80.64% ± 1.47% and 14.07% ± 0.95% of administered radioactivity were recovered in urine and feces, respectively, in intact rats over 120 h. The mean areas under the plasma concentration-time curve was (8818.4 ± 576.1) Bq/h/mL. The results of tissue distribution, excretion and pharmacokinetics of R-hap in rats provided biopharmaceutical basis for the design of future clinical trials.展开更多
Land surface models are often highly nonlinear with model physics that contain parameterized discontinuities. These model attributes severely limit the application of advanced variational data assimilation methods int...Land surface models are often highly nonlinear with model physics that contain parameterized discontinuities. These model attributes severely limit the application of advanced variational data assimilation methods into land data assimilation. The ensemble Kalman filter (EnKF) has been widely employed for land data assimilation because of its simple conceptual formulation and relative ease of implementation. An updated ensemble-based three-dimensional variational assimilation (En3-DVar) method is proposed for land data assimilation.This new method incorporates Monte Carlo sampling strategies into the 3-D variational data assimilation framework. The proper orthogonal decomposition (POD) technique is used to efficiently approximate a forecast ensemble produced by the Monte Carlo method in a 3-D space that uses a set of base vectors that span the ensemble. The data assimilation process is thus significantly simplified. Our assimilation experiments indicate that this new En3-DVar method considerably outperforms the EnKF method by increasing assimilation precision. Furthermore, computational costs for the new En3-DVar method are much lower than for the EnKF method.展开更多
This field study sought to determine the all-weather surface construction providing the least contaminated runoff and drainage effluent when exposed to moderate to heavy precipitation and different manure loads in hor...This field study sought to determine the all-weather surface construction providing the least contaminated runoff and drainage effluent when exposed to moderate to heavy precipitation and different manure loads in horse paddocks during wintertime. Two different combinations of non-woven and woven geotextile together with two gravel fractions of 200 nlm were exposed to precipitation and horse manure/urine for two years under two manure regimes (manure removal and manure accumulation). In a simulated rainfall (SR) study, the test areas were also exposed to 50 mm precipitation for 30 min and 15 kg of horse manure under the two manure regimes. Runoff, drainage effluent and leachate flow were measured and sampled for both regimes. The geotextile-gravel construction reduced runoff and drained the test area throughout the two-year period, confirming construction stability and a dry walking surface area at a mean drain flow of 3.65 L m2 h1. The concentrations of total N, total phosphorus (TP), chemical oxygen demand (COD) and total solids (TS) in fluids leaving the test areas in winter were lower than in previous studies, due to lower horse density. The mean drainage concentration of TP, COD and TS was 3.4, 231, 739 mg L1, respectively, due to manure removal in the SR study. The TP (1.9 mg L-1) concentration in drain fluids was reduced by 47% in the test area consisting of a single geotextile compared with previously reported values (3.6 mg Ll). With the paddock designs tested here, non-point pollution from paddocks could be controlled and reduced.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
Brucine has anti-inflammatory and analgesic effects and is the main active compound of the seeds of Strychnos nux-vomica L. To study brucine niosomal gels, a reliable and rapid LC-MS/MS method was established to quant...Brucine has anti-inflammatory and analgesic effects and is the main active compound of the seeds of Strychnos nux-vomica L. To study brucine niosomal gels, a reliable and rapid LC-MS/MS method was established to quantify brucine levels in rats. Tissue distribution and pharmacokinetics of brucine were investigated after topical and oral application of brucine niosomal gels to rats. The plasma concentration versus time profiles suggested that systemic exposure of brucine for oral administration of brucine niosomal gels was higher than that for topical administration, and topical administration showed a relatively sustained release. There was a considerable amount of brucine distributed in the knee joint. These results provided a strong basis for the follow-up study of this preparation.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
文摘Aim To measure the penetration of capecitabine from the plasma into tissue and to investigate the pharmacokinetics of its metabolizing into fluorouracil (5-FU) in patients with advanced breast cancer. Methods Twenty-seven patients with breast cancer received repeated doses of 1 255 mg·m^-2 of capecitabine twice daily for 7 d. Blood, tumor, and adjacent healthy tissue samples were collected. The concentrations of capecitabine and its metabolite 5-FU were determined by HPLC. The concentration-time profiles of capecitabine and 5-FU were fitted by pharmacokinetic model. The tissue distribution factors for capecitabine and 5-FU, and the AUC ratios of 5-FU to capecitabine in plasma, tumor or adjacent healthy tissue, were calculated with pharmacokinetic parameters, respectively. Results The Ka of capecitabine was 1.17 h^-1 in plasma, 0. 46 h^-1 in tumor tissue, and 0. 61 h^-1 in healthy tissue. The AUCs of capecitabine were 2. 557 1 μg·mL^-1 ·h, 1. 629 2 μg·g^-1·h and 2. 085 0 μg·g^-1· h, and T1/2 was 0. 782 3 h, 1. 528 1 h and 1. 289 6 h in plasma, tumor, and healthy tissue, respectively. The AUCs of 5-FU were 0.418 7 μg·mL^-1 h, 1.671 7 μg·g^-1·h and 1.020 8 μg·g^-1·h; the T1/2 was 0. 631 3 h ,1.204 1 h and 1.031 2 h in plasma, tumor, and healthy tissue, respectively. The tissue distribution factors of capecitabine were 0. 637 1 in tumor (AUCcap-Tumor/AUCcap-plasma) and 0. 851 4 in healthy tissue (AUCcap-HT/AUCcap-plasma . The tissue distribution factors of 5-FU were 3. 992 6 in tumor (AUC5-FU-Tumor/AUC5-FU-plasma) and 2. 438 0 in healthy tissue (AUC5-FU-HT/AUC5-FU-plasma). The AUC ratios of 5-FU to capecitabine were 0. 1637, 1. 0261, and 0. 489 5 in plasma, tumor, and healthy tissue, respectively. Conclusion The simulation curves for the disposition of capecitabine and its metabolite 5-FU in plasma and tissue basically describe the activation process of capecitabine metabolizing to 5-FU and 5-FU elimination. There are similar distributions for capecitabine in plasma, tumor, and healthy tissue. The exposure of 5-FU in tumor was found to be 3. 992 6 times greater than that in plasma and 2. 438 0 times greater than that in healthy tissue. Capecitabine may metabolize preferentially to 5- FU in tumor tissue after oral administration.
基金Supported by Financial Project from Ministry of Agriculture(2014-2130135)Specia Fund for Basal Scientific Research of Central Public-interest Scientific Institutes,Beijing Institute of Animal Husbandry and Veterinary,Chinese Academy of Agricultura Sciences(2014ywf-yb-7)~~
文摘Myocyte enhancer factor 2B (MEF2B) gene belongs to myocyte enhancer factor 2 (MEF2) gene family. They are all widely expressed in muscle and nerve tissues of human and animals. MEF2B plays an important role in the growth of muscle, development and differentiation of nerve system and liver fibrosis. This re- view mainly focused on the structural characteristics, tissue distribution, biological functions and research progress of MEF2B gene in human and animals.
基金National Natural Sciences Foundation of China(Grant No.30371669)National High Technology Research and Development Program of China(863 Program,Grant No.2003AA2Z347B).
文摘The purpose of this study is to characterize the tissue distribution, excretion and pharmacokinetics profiles of R-hap in healthy Wistar rats. R-hap was radiolabeled by the IODO-GEN method. Tissue distribution and urinary, fecal and biliary excretion patterns of ^125I-R-hap were investigated following a single i.v. bolus injection. Pharmacokinetics properties of ^125I-R-hap were also examined after a single i.v. bolus injection. The trichloroacetic acid (TCA) precipitated radioactivity was widely distributed and rapiclly diminished in most tissues. Kidney contained the highest radioactivity among all organs and the distribution of ^125I-R-hap to fat was minimal. The cumulative excretion of ^125I-R-hap reached 71.81% ± 2.15% of the administered radioactivity at 48 h and 94.71% ± 1.50% at 120 h. Urinary excretion was the dominant route of elimination following i.v. administration, as 80.64% ± 1.47% and 14.07% ± 0.95% of administered radioactivity were recovered in urine and feces, respectively, in intact rats over 120 h. The mean areas under the plasma concentration-time curve was (8818.4 ± 576.1) Bq/h/mL. The results of tissue distribution, excretion and pharmacokinetics of R-hap in rats provided biopharmaceutical basis for the design of future clinical trials.
基金supported by the National Natural Science Foundation of China (Grant No. 40705035)the National High Technology Research and Development Program of China (863 Program) (Grant Nos. 2009AA12Z129 and 2007AA12Z144)
文摘Land surface models are often highly nonlinear with model physics that contain parameterized discontinuities. These model attributes severely limit the application of advanced variational data assimilation methods into land data assimilation. The ensemble Kalman filter (EnKF) has been widely employed for land data assimilation because of its simple conceptual formulation and relative ease of implementation. An updated ensemble-based three-dimensional variational assimilation (En3-DVar) method is proposed for land data assimilation.This new method incorporates Monte Carlo sampling strategies into the 3-D variational data assimilation framework. The proper orthogonal decomposition (POD) technique is used to efficiently approximate a forecast ensemble produced by the Monte Carlo method in a 3-D space that uses a set of base vectors that span the ensemble. The data assimilation process is thus significantly simplified. Our assimilation experiments indicate that this new En3-DVar method considerably outperforms the EnKF method by increasing assimilation precision. Furthermore, computational costs for the new En3-DVar method are much lower than for the EnKF method.
文摘This field study sought to determine the all-weather surface construction providing the least contaminated runoff and drainage effluent when exposed to moderate to heavy precipitation and different manure loads in horse paddocks during wintertime. Two different combinations of non-woven and woven geotextile together with two gravel fractions of 200 nlm were exposed to precipitation and horse manure/urine for two years under two manure regimes (manure removal and manure accumulation). In a simulated rainfall (SR) study, the test areas were also exposed to 50 mm precipitation for 30 min and 15 kg of horse manure under the two manure regimes. Runoff, drainage effluent and leachate flow were measured and sampled for both regimes. The geotextile-gravel construction reduced runoff and drained the test area throughout the two-year period, confirming construction stability and a dry walking surface area at a mean drain flow of 3.65 L m2 h1. The concentrations of total N, total phosphorus (TP), chemical oxygen demand (COD) and total solids (TS) in fluids leaving the test areas in winter were lower than in previous studies, due to lower horse density. The mean drainage concentration of TP, COD and TS was 3.4, 231, 739 mg L1, respectively, due to manure removal in the SR study. The TP (1.9 mg L-1) concentration in drain fluids was reduced by 47% in the test area consisting of a single geotextile compared with previously reported values (3.6 mg Ll). With the paddock designs tested here, non-point pollution from paddocks could be controlled and reduced.
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National Science and Technology Major Projects for"Major New Drugs Innovation and Development"(Grant No.2017ZX09301016)
文摘Brucine has anti-inflammatory and analgesic effects and is the main active compound of the seeds of Strychnos nux-vomica L. To study brucine niosomal gels, a reliable and rapid LC-MS/MS method was established to quantify brucine levels in rats. Tissue distribution and pharmacokinetics of brucine were investigated after topical and oral application of brucine niosomal gels to rats. The plasma concentration versus time profiles suggested that systemic exposure of brucine for oral administration of brucine niosomal gels was higher than that for topical administration, and topical administration showed a relatively sustained release. There was a considerable amount of brucine distributed in the knee joint. These results provided a strong basis for the follow-up study of this preparation.
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.