Biopharmaceutics and Pharmacokinetics of Timosaponin A-III by a Sensitive HPLC-MS/MS Method: Low Bioavailability Resulting from Poor Permeability and Solubility

2020 ◽  
Vol 21 ◽  
Author(s):  
Hai-Qiao Wang ◽  
Xiao-Mei Gong ◽  
Fen Lan ◽  
Yi-Han Zhang ◽  
Jin-Er Xia ◽  
...  
Keyword(s):  
Rat Liver ◽  
Oral Bioavailability ◽  
Liver Microsome ◽  
Transport Model ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Absolute Oral Bioavailability ◽  
Rat Liver Microsome

Background: Timosaponin A-III is one of the most promising active saponins from Anemarrhena asphodeloides Bge. As an oral chemotherapeutic agent, there is an urgent need to clarify its biopharmaceutics and pharmacokinetics to improve its development potential. Objective: This research explores the bioavailability of timosaponin A-III and clarifies its absorption and metabolism mechanisms by a sensitive and specific HPLC-MS/MS method. Methods: Pharmacokinetics and bioavailability studies of timosaponin A-III were performed in Sprague-Dawley rats by oral (20 g/kg) and intravenous administration (2 mg/kg). Control group was given the same volume of normal saline. The absorption of timosaponin A-III was investigated in a rat intestinal perfusion model in situ and a Caco-2 cell transport model in vitro. The metabolic rate of timosaponin A-III was determined in a rat liver microsome incubation system. Results: After the oral administration, timosaponin A-III reached Cmax of 120.90 ± 24.97 ng/mL at 8 h, and the t1/2 was 9.94 h. The absolute oral bioavailability of timosaponin A-III is 9.18%. The permeability coefficients of timosaponin A-III in four intestinal segments ranged from 4.98 to 5.42 cm/s, indicating a difficult absorption. A strikingly high transport of timosaponin A-III was found, PappBA 3.27 ± 0.64 × 10−6 cm/s, which was abolished by a P-gp inhibitor. Rat liver microsome incubation studies showed that timosaponin A-III could hardly be metabolized, with a t1/2 of over 12 h. In addition, the solubility test showed a low solubility in PBS solution, 30.58 μg/mL. Conclusion: Timosaponin A-III exhibited low oral bioavailability by oral and intravenous admiConclusion: nistration, which was probably caused by its low permeability and solubility. This study may provide a reference for the rational clinical use and further study on the pharmacology or toxicology of timosaponin A-III.

Inhibitory Effect of Resveratrol on the Pharmacokinetics of Ticagrelor in Vivo and Vitro

2021 ◽  
Author(s):  
Peng Wang ◽  
Xiao-Xia Hu ◽  
Ying-hui Li ◽  
Nan-Yong Gao ◽  
Guo-quan Chen ◽  
...  
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
In Vitro Study ◽  
Inhibitory Effect ◽  
Control Group ◽  
Rat Liver Microsomes ◽  
Sprague Dawley ◽  
Group B

This study was to evaluate the effect of resveratrol on the pharmacokinetics of ticagrelor in rats and the metabolism of ticagrelor in human CYP3A4 and liver microsomes. Eighteen Sprague-Dawley rats were randomly divided into three groups: group A (control group), group B (50mg/kg resveratrol), and group C (150mg/kg resveratrol ). After 30 minutes administration of resveratrol, a single dose of ticagrelor (18mg/kg) was administered orally. The vitro experiment was performed to examine the influence of resveratrol on ticagrelor metabolism in CYP3A4*1, human, and rat liver microsomes. Serial biological samples were assayed by validated UHPLC-MS/MS methods. In vivo study, the AUC and Cmax of ticagrelor in group B and C appeared to be significantly higher than the control group, while Vz/F and CLz/F of ticagrelor in group B and C were significantly decreased. In vitro study, resveratrol exhibited an inhibitory effect on CYP3A4*1, human and rat liver microsomes. The IC50 values of resveratrol were 56.75μM，69.07μM and 14.22μM, respectively. Our results indicated that resveratrol had a inhibitory effect on the metabolism of ticagrelor in vitro and vivo. It should be paid more attention to the clinical combination of resveratrol with ticagrelor and ticagrelor plasma concentration should be monitored to avoid the occurrence of adverse reaction.

Inhibitory effect of silybin on pharmacokinetics of imatinib in vivo and in vitro

2014 ◽  
Vol 92 (11) ◽  
pp. 961-964 ◽  
Author(s):  
Li Wang ◽  
Zhe Wang ◽  
Meng-ming Xia ◽  
Ying-ying Wang ◽  
Hai-yun Wang ◽  
...  
Keyword(s):  
Single Dose ◽  
Rat Liver ◽  
Liver Microsome ◽  
Liver Microsomes ◽  
Inhibitory Effect ◽  
Pharmacokinetic Parameters ◽  
Control Group ◽  
Rat Liver Microsomes ◽  
Multiple Doses

The objective of this work was to investigate the effect of orally administered silybin on the pharmacokinetics of imatinib in rats and the metabolism of imatinib in human liver microsome and rat liver microsomes. Eighteen healthy male SD rats were randomly divided into 3 groups: group A (control group), group B (received multiple doses of 50 mg·kg−1 silybin for 15 consecutive days), and group C (received a single dose of 50 mg·kg−1 silybin). A single dose of imatinib was administered orally 30 min after administration of silybin (50 mg·kg−1). Imatinib plasma levels were measured by UPLC-MS/MS, and pharmacokinetic parameters were calculated by DAS 3.0 software (Bontz Inc., Beijing, China). In addition, human and rat liver microsome were performed to determine the effects of silybin metabolism of imatinib in vitro. The multiple doses or single dose of 50 mg·kg−1 silybin significantly decreased the area under the curve (0-t) of imatinib (p < 0.01). And the half-life (t1/2) of imatinib is significantly increased (p < 0.05 and p < 0.01, respectively). Also, silybin showed inhibitory effect on human and rat microsomes, the IC50 of silybin were 26.42 μmol·L−1 and 49.12 μmol·L−1 in human and rat liver microsomes, respectively. These results indicate that more attention should be paid to when imatinib is administrated combined with silybin.

scholarly journals A Novel Strategy to Enhance Microfracture Treatment With Stromal Cell-Derived Factor-1 in a Rat Model

2021 ◽  
Vol 8 ◽  
Author(s):  
Taylor Mustapich ◽  
John Schwartz ◽  
Pablo Palacios ◽  
Haixiang Liang ◽  
Nicholas Sgaglione ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cartilage Repair ◽  
Osteochondral Defect ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Stromal Cell Derived Factor ◽  
Empty Control

BackgroundMicrofracture is one of the most widely used techniques for the repair of articular cartilage. However, microfracture often results in filling of the chondral defect with fibrocartilage, which exhibits poor durability and sub-optimal mechanical properties. Stromal cell-derived factor-1 (SDF-1) is a potent chemoattractant for mesenchymal stem cells (MSCs) and is expressed at high levels in bone marrow adjacent to developing cartilage during endochondral bone formation. Integrating SDF-1 into an implantable collagen scaffold may provide a chondro-conductive and chondro-inductive milieu via chemotaxis of MSCs and promotion of chondrogenic differentiation, facilitating more robust hyaline cartilage formation following microfracture.ObjectiveThis work aimed to confirm the chemoattractive properties of SDF-1 in vitro and develop a one-step method for incorporating SDF-1 in vivo to enhance cartilage repair using a rat osteochondral defect model.MethodsBone marrow-derived MSCs (BMSCs) were harvested from the femurs of Sprague–Dawley rats and cultured in low-glucose Dulbecco’s modified Eagle’s medium containing 10% fetal bovine serum, with the medium changed every 3 days. Passage 1 MSCs were analyzed by flow cytometry with an S3 Cell Sorter (Bio-Rad). In vitro cell migration assays were performed on MSCs by labeling cells with carboxyfluorescein diacetate, succinimidyl ester (CFDA-SE; Bio-Rad). For the microfracture model, a 1.6-mm-diameter osteochondral defect was created in the femoral trochleae of 20 Sprague–Dawley rats bilaterally until bone marrow spillage was seen under saline irrigation. One knee was chosen at random to receive implantation of the scaffold, and the contralateral knee was left unfilled as an empty control. Type I collagen scaffolds (Kensey Nash) were coated with either gelatin only or gelatin and SDF-1 using a dip coating process. The rats received implantation of either a gelatin-only scaffold (N = 10) or gelatin-and-SDF-1 scaffold (N = 10) at the site of the microfracture. Femurs were collected for histological analyses at 4- and 8-week time points post-operatively, and sections were stained with Safranin O/Fast Green. The samples were graded blindly by two observers using the Modified O’Driscoll score, a validated scoring system for chondral repair. A minimum of 10 separate grading scores were made per sample and averaged. Quantitative comparisons of cell migration in vitro were performed with one-way ANOVA. Cartilage repair in vivo was also compared among groups with one-way ANOVA, and the results were presented as mean ± standard deviation, with P-values &lt; 0.05 considered as statistically significant.ResultsMSC migration showed a dose–response relationship with SDF-1, with an optimal dosage for chemotaxis between 10 and 100 ng/ml. After scaffold implantation, the SDF-1-treated group demonstrated complete filling of the cartilage defect with mature cartilage tissue, exhibiting strong proteoglycan content, smooth borders, and good incorporation into marginal cartilage. Modified O’Driscoll scores after 8 weeks showed a significant improvement of cartilage repair in the SDF-1 group relative to the empty control group (P &lt; 0.01), with a trend toward improvement when compared with the gelatin-only-scaffold group (P &lt; 0.1). No significant differences in scores were found between the empty defect group and gelatin-only group.ConclusionIn this study, we demonstrated a simple method for improving the quality of cartilage defect repair in a rat model of microfracture. We confirmed the chemotactic properties of SDF-1 on rat MSCs and found an optimized dosage range for chemotaxis between 10 and 100 ng/ml. Furthermore, we demonstrated a strategy to incorporate SDF-1 into gelatin–collagen I scaffolds in vivo at the site of an osteochondral defect. SDF-1-treated defects displayed robust hyaline cartilage resurfacing of the defect with minimal fibrous tissue, in contrast to the empty control group. The results of the in vitro and in vivo studies together suggest that SDF-1-mediated signaling may significantly improve the quality of cartilage regeneration in an osteochondral defect.

Biopharmaceutical and pharmacokinetic activities of oxymatrine determined by a sensitive UHPLC-MS/MS method

2021 ◽  
Vol 22 ◽  
Author(s):  
Hai-Qiao Wang ◽  
Feng-Hua Chen ◽  
Liang Wang ◽  
Li-Qun Chi ◽  
Guang-Hua Wang
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Passive Diffusion ◽  
Pharmacokinetic Parameters ◽  
Rat Liver Microsomes ◽  
Absorption Model ◽  
Absolute Oral Bioavailability ◽  
Rat Liver Microsome

Background: Oxymatrine is one of the most promising alkaloids from Sophora flavescens for its excellent pharmacological effects. Objective: The aim of this research is to assess the biopharmaceutical and pharmacokinetic activities of oxymatrine, and clarify its mechanisms of absorption and metabolism. Methods: The biological characteristics of oxymatrine were systematically investigated by UHPLC-MS/MS. The mechanisms of absorption and metabolism of oxymatrine were further clarified through incubation in rat liver microsomes and transport across Caco-2 monolayer cell absorption model. Results: It was found that the absolute oral bioavailability of oxymatrine was 26.43% and the pharmacokinetic parameters Cmax, Tmax, and t1/2 were 605.5 ng/mL, 0.75 h, and 4.181 h after oral administration, indicating that oxymatrine can be absorbed quickly. The tissue distribution tests showed that oxymatrine distributed throughout all the organs, with the small intestine accumulating the highest level followed by kidney, stomach and spleen. The Papp in Caco-2 cell line absorption model was over 1 × 10-5 and PDR 1.064, t1/2 of oxymatrine in rat liver microsome in vitro was 1.042 h, indicating that oxymatrine can be absorbed easily through passive diffusion and CYP450 enzymes could be involved in its metabolism. The plasma protein binding rate of oxymatrine was 2.78 ± 0.85%. Conclusion: Oxymatrine can be absorbed into blood easily through passive diffusion, mainly distributed in the intestine, stomach, liver and spleen in vivo, and CYP450 enzymes in liver could be involved in its metabolism.

Papillary mechanics and cardiac morphology of infarcted rat hearts after training

1987 ◽  
Vol 63 (1) ◽  
pp. 92-96 ◽  
Author(s):  
D. L. Geenen ◽  
T. P. White ◽  
R. M. Lampman
Keyword(s):  
Maximum Rate ◽  
Adenosine Triphosphatase ◽  
Left Ventricular ◽  
Control Group ◽  
Sprague Dawley ◽  
Force Development ◽  
Sprague Dawley Rats ◽  
Rat Hearts ◽  
Physiological Adaptations

Infarction of the left ventricle was induced by ligation of the coronary artery in male Sprague-Dawley rats under ketamine-xylazine anesthesia. Three weeks after surgery, animals were assigned to a trained (n = 21; running at 20 m/min, 10% grade, 1 h/day, 5 days/wk) or nontrained group (n = 23) for an additional 8 wk. A third, sham-operated control group (n = 16) remained cage sedentary for 11 wk. Ventricular mass was greater in the trained and nontrained infarct groups [1,335 +/- 57.3 and 1,414 +/- 56.1 mg, respectively (mean +/- SE)] compared with the control group (1,155 +/- 50.9 mg) (P less than or equal to 0.05). The diameter of septal fibers was 13% greater in the trained and 17% greater in the nontrained infarct groups compared with control. The specific peak developed force and maximum rate of force development of left ventricular papillary muscle in vitro were 75 and 62% greater in both infarcted groups compared with the control group; these variables were unaffected by training. Myofibrillar adenosine triphosphatase activity of septum was 20% lower in both infarct groups compared with sham-operated animals. We conclude that exercise training did not alter the magnitude of morphological and physiological adaptations to infarction.

Cytochrome C suppresses renal accumulation and nephrotoxicity of polymyxin B

2018 ◽  
Vol 38 (2) ◽  
pp. 193-200 ◽  
Author(s):  
Z-D Li ◽  
J Luo ◽  
L-H Jia ◽  
X-Y Wang ◽  
Z-K Xun ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Polymyxin B ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
C 30 ◽  
C 50

The receptor megalin plays an important role in the accumulation of polymyxin B (PMB) in renal cells in vitro. This study aimed to examine the effects of cytochrome c (cyto c), a typical megalin ligand, on renal accumulation and nephrotoxicity of PMB in vivo. Thirty Sprague-Dawley rats were randomly divided into the vehicle control group, PMB group, PMB + cyto c 50, 100, or 200 mg/kg group, respectively, and were treated with intravenous cyto c 30 min before the administration of PMB 4.0 mg/kg once a day for consecutive 5 days. On the 4th day after administration, 24 h urine was collected to determine N-acetyl-β-D-glucosaminidase excretion. Six hours after the last injection on the 5th day, kidneys were harvested to assay PMB concentration and observe pathological alterations, and blood samples were collected to assay serum creatinine (SCr), blood urea nitrogen (BUN), and blood β2-microglobulin (β2-MG) levels. Cyto c 50, 100, and 200 mg/kg decreased the accumulation of PMB in the kidney by 18.5%, 39.1% ( p < 0.01), and 36.8% ( p < 0.01), respectively, and reduced 24 h N-acetyl-β-D- glucosaminidase excretion by 22.5% ( p < 0.05), 40.4% ( p < 0.01), and 40.4% ( p < 0.01), respectively. Kidney pathological damage induced by PMB was markedly reduced by cyto c 100 mg/kg and 200 mg/kg. However, there were no significant differences in SCr, BUN, and blood β2-MG levels among the groups. These results indicated that cyto c may inhibit the renal accumulation and nephrotoxicity of PMB in a rat model, further proving the role of megalin in the accumulation of PMB.

scholarly journals Chilean Strawberry Consumption Protects against LPS-Induced Liver Injury by Anti-Inflammatory and Antioxidant Capability in Sprague-Dawley Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Sebastian Molinett ◽  
Francisca Nuñez ◽  
María Alejandra Moya-León ◽  
Jessica Zúñiga-Hernández
Keyword(s):  
Liver Injury ◽  
Aqueous Extract ◽  
Inflammatory Responses ◽  
Animal Health ◽  
Antioxidant Properties ◽  
Serum Levels ◽  
Control Group ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

The Chilean strawberry fruit has high content of antioxidants and polyphenols. Previous studies evidenced antioxidant properties byin vitromethods. However, the antioxidant effect and its impact as functional food on animal health have not been evaluated. In this study, rats were fed with a Chilean strawberry aqueous extract (4 g/kg of animal per day) and then subjected to LPS-induced liver injury (5 mg/kg). Transaminases and histological studies revealed a reduction in liver injury in rats fed with strawberry aqueous extract compared with the control group. Additionally, white strawberry supplementation significantly reduced the serum levels and gene expression of TNF-α, IL-6, and IL-1βcytokines compared with nonsupplemented rats. The level of F2-isoprostanes and GSH/GSSG indicated a reduction in liver oxidative stress by the consumption of strawberry aqueous extract. Altogether, the evidence suggests that dietary supplementation of rats with a Chilean white strawberry aqueous extract favours the normalization of oxidative and inflammatory responses after a liver injury induced by LPS.

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