scholarly journals Pharmacokinetic Study of Di-Phenyl-Di-(2,4-Difluobenzohydroxamato)Tin(IV): Novel Metal-Based Complex with Promising Antitumor Potential

2012 ◽  
Vol 2012 ◽  
pp. 1-8
Author(s):  
Yunlan Li ◽  
Zhuyan Gao ◽  
Pu Guo ◽  
Qingshan Li
Keyword(s):  
Internal Standard ◽  
Compartment Model ◽  
Rat Plasma ◽  
Hplc Method ◽  
Array Detector ◽  
Concentration Time ◽  
Two Compartment Model ◽  
Photodiode Array Detector

Di-phenyl-di-(2,4-difluobenzohydroxamato)tin(IV)(DPDFT), a new metal-based arylhydroxamate antitumor complex, showed highin vivoandin vitroantitumor activity with relative low toxicity, but no data was reported regarding its pharmacokinetics and dependent toxicity. In this paper, a rapid, sensitive, and reproducible HPLC methodin vivousing Diamonsil ODS column with a mixture of methanol and phosphoric acid in water (30 : 70, V/V, pH 3.0) as mobile phase was developed and validated for the determination of DPDFT. The plasma was deproteinized with methanol that contained acetanilide as the internal standard (I.S.). The photodiode array detector was set at a wavelength of 228 nm at room temperature and a linear curve over the concentration range 0.1~25 μg·mL-1(r= 0.9993) was obtained. The method was used to determine the concentration-time profiles for DPDFT in the plasma after single intravenous administration with doses of 5, 10, 15 mg·kg-1to rats. The pharmacokinetics parameter calculations and modeling were carried out using the 3p97 software. The results showed that the concentration-time curves of DPDFT in rat plasma could be fitted to two-compartment model.

scholarly journals Development and Validation of a Sensitive UHPLC-MS/MS Method for the Measurement of Gardneramine in Rat Plasma and Tissues and its Application to Pharmacokinetics and Tissue Distribution Study

Molecules ◽  
2019 ◽  
Vol 24 (21) ◽  
pp. 3953 ◽  
Author(s):  
Zhao ◽  
Tan ◽  
Chen ◽  
Sun ◽  
Wang ◽  
...  
Keyword(s):  
Multiple Reaction Monitoring ◽  
Indole Alkaloid ◽  
Internal Standard ◽  
Gradient Elution ◽  
Rat Plasma ◽  
Limit Of Quantification ◽  
Tissue Samples ◽  
Distribution Study

As a novel monoterpenoid indole alkaloid, gardneramine has been confirmed to possess excellent nervous depressive effects. However, there have been no reports about the measurement of gardneramine in vitro and in vivo. The motivation of this study was to establish and validate a specific, sensitive, and robust analytical method based on UHPLC-MS/MS for quantification of gardneramine in rat plasma and various tissues after intravenous administration. The analyte was extracted from plasma and tissue samples by protein precipitation with methanol using theophylline as an internal standard (I.S.). The analytes were separated on an Agilent ZORBAX Eclipse Plus C18 column using a gradient elution of acetonitrile and 0.1% formic acid in water at a flow rate of 0.3 mL/min. Gardneramine and I.S. were detected and quantified using positive electrospray ionization in multiple reaction monitoring (MRM) mode with transitions of m/z 413.1→217.9 for gardneramine and m/z 181.2→124.1 for I.S.. Perfect linearity range was 1–2000 ng/mL with a correlation coefficient (r2) of ≥0.990. The lower limit of quantification (LLOQ) of 1.0 ng/mL was adequate for application to different preclinical studies. The method was successfully applied for determination of gardneramine in bio-samples.

Single Dose Administration of rFVIIa and NN1731 in Two Hemophilia A Dogs.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3144-3144 ◽  
Author(s):  
Mirella Ezban ◽  
Lone Frost ◽  
Dorthe Viuff ◽  
Judi Møss ◽  
Mark Kloos ◽  
...  
Keyword(s):  
Hemophilia A ◽  
Ex Vivo ◽  
Compartment Model ◽  
Initial Distribution ◽  
Coagulation Assays ◽  
Two Compartment Model ◽  
Dose Study ◽  
Related Proteins

Abstract Introduction: The objective of this pilot study was to evaluate and compare the pharmacokinetic and pharmacodynamic (PK/PD) profile of rFVIIa and NN1731 in two hemophilia A dogs. In addition, it was the aim to evaluate the use of TEG for monitoring rFVIIa/NN1731 activity after in vivo administration and to compare with ex vivo spiking data from a previous study. NN1731 is a new rFVIIa analoge with enhanced activity (Allen et al. Arterioscler. Thromb. Vasc. Biol.2007;27:683–689). In hemophilia patients as well as hemophilia dogs the clot formation is impaired and reflected in coagulation assays such as thromboelastography (TEG) and APTT. The choice of hemophilia dogs is based upon the knowledge that the pharmacokinetics of human coagulations factors (FVIII, FIX and rFVIIa) as well as the effective dose is similar to that in humans. In normal dogs, it is not possible to evaluate the effect of these procoagulant proteins in coagulation assays as no impaired clotting is observed. Methods: rFVIIa and NN1731 (280 μg/kg IV) were administered to two hemophilia dogs on separate days and plasma samples collected at different time points. FVIIa activity was measured by the FVIIa clot assay and values were used for pharmacokinetic assessment. The same pharmacokinetic models, a non-compartmental method and a two compartment model, respectively, were used as was the case in the First Human Dosing (FHD) trial of NN1731 (NN1731–1639). Analysis of PD markers in dogs included: APTT, PT and whole blood thromboelastography analysis, recently developed for use in hemophilia dogs. Results: Based on the FVIIa activity profile in the two dogs it was observed that the values obtained at the first time point (C5 min), were higher after treatment with NN1731 than after rFVIIa. All activity based assays including TEG demonstrated that NN1731 was cleared faster than rFVIIa., FVIIa activity (FVIIa clot assay), showed a rapid initial distribution and/or elimination of FVIIa activity (t1/2α:0.3 h) followed by a less rapid elimination phase (t½β:3.5 h). Similar profile and values were obtained for NN1731 in the FHD dose study (J. Møss et al, ISTH, 2007) Conclusions: This study indicates that in hemophilia A dogs, NN1731 and rFVIIa have distinct PK profiles and very similar to what is observed in man. All activity assays show the same qualitative profile, the FVIIa clot assay being the most sensitive assay. The TEG data obtained in vivo are in accordance with the values obtained after in vitro spiking. The data support the use of hemophilia dogs for evaluating the pharmacokinetic and pharmacodynamic profiles of FVIIa related proteins.

scholarly journals Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Support Dose Selection for ME1100, an Arbekacin Inhalation Solution

2020 ◽  
Vol 64 (10) ◽  
Author(s):  
Sujata M. Bhavnani ◽  
Jeffrey P. Hammel ◽  
Elizabeth A. Lakota ◽  
M. Courtney Safir ◽  
Brian D. VanScoy ◽  
...  
Keyword(s):  
Compartment Model ◽  
Simulated Patients ◽  
Population Pharmacokinetic ◽  
Total Drug ◽  
Target Attainment ◽  
Time Curve ◽  
Content Type ◽  
Concentration Time

ABSTRACT ME1100 (arbekacin inhalation solution) is an inhaled aminoglycoside that is being developed to treat patients with hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively). Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were undertaken to evaluate ME1100 regimens for the treatment of patients with HABP/VABP. The data used included a population pharmacokinetic (PPK) 4-compartment model with 1st-order elimination, nonclinical PK-PD targets from one-compartment in vitro and/or in vivo infection models, and in vitro surveillance data. Using the PPK model, total-drug epithelial lining fluid (ELF) concentration-time profiles were generated for simulated patients with varying creatinine clearance (CLcr) (ml/min/1.73 m2) values. Percent probabilities of PK-PD target attainment by MIC were determined based on the ratio of total-drug ELF area under the concentration-time curve (AUC) to MIC (AUC/MIC ratio) targets associated with 1- and 2-log10 CFU reductions from baseline for Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus. Percent probabilities of PK­PD target attainment based on PK-PD targets for a 1-log10 CFU reduction from baseline at MIC values above the MIC90 value for K. pneumoniae (8 μg/ml), P. aeruginosa (4 μg/ml), and S. aureus (0.5 μg/ml) were ≥99.8% for ME1100 600 mg twice daily (BID) in simulated patients with CLcr values >80 to ≤120 ml/min/1.73 m2. ME1100 600 mg BID, 450 mg BID, and 600 mg once daily in simulated patients with CLcr values >50 to ≤80, >30 to ≤50, and 0 to ≤30 ml/min/1.73 m2, respectively, provided arbekacin exposures that best matched those for 600 mg BID in simulated patients with normal renal function. These data provide support for ME1100 as a treatment for patients with HABP/VABP.

scholarly journals Pharmacokinetic and Bioavailability Studies of Embelin after Intravenous and Oral Administration to Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Zhen Li ◽  
Shu-jing Chen ◽  
Xie-an Yu ◽  
Jin Li ◽  
Xiu-mei Gao ◽  
...  
Keyword(s):  
Phosphoric Acid ◽  
Oral Bioavailability ◽  
High Performance ◽  
Internal Standard ◽  
Rat Plasma ◽  
Hepatoprotective Activity ◽  
Array Detector ◽  
Limit Of Quantification ◽  
Intravenous And Oral Administration

Embelin exhibits the broad bioactivities such as antitumor, antifertility, antidiabetic, anti-inflammatory, antioxidant, anticonvulsant, anxiolytic, antimicrobial, and hepatoprotective activity. In order to further understand the pharmacokinetic characteristics and oral bioavailability of embelin in vivo, the concentration of embelin in rat plasma was determined by a sensitive high-performance liquid chromatography with diode array detector (HPLC-DAD). The preparation of samples was accomplished by a simple precipitating protein with methanol. Emodin was selected as the internal standard (IS). Embelin and IS were completely separated on an analytical column (Extend-C18, 4.6 × 250 mm, 5 μm) using 0.1% phosphoric acid in methanol and 0.1% phosphoric acid in aqueous solution (90:10, v/v) as the mobile phase. The lower limit of quantification was 0.15 μg/mL. Oral bioavailability of embelin was 30.2 ± 11.9%. This study could provide the information about pharmacokinetics and oral bioavailability of embelin, which was useful to assess the clinic efficacy and safety and promote further development of embelin.

scholarly journals In Vitro and In Vivo Evaluation of Two Hydroxychloroquine Tablet Formulations: HPLC Assay Development

2020 ◽  
Vol 59 (1) ◽  
pp. 71-78
Author(s):  
Jaber Emami ◽  
Moloud Kazemi ◽  
Anahita Salehi
Keyword(s):  
High Performance ◽  
Internal Standard ◽  
Reversed Phase ◽  
Hplc Method ◽  
In Vivo Studies ◽  
Crossover Fashion ◽  
Content Uniformity ◽  
In Vivo Evaluation

Abstract The relative in vitro and in vivo evaluation of two hydroxychloroquine (HCQ) products was conducted. In vitro studies involved assay, content uniformity and dissolution test, and a two-way crossover fashion were used for in vivo studies. Blood samples were collected at appropriate intervals and HCQ levels were measured using a validated reversed-phase high-performance liquid chromatography (HPLC) method. The drug and the internal standard, chloroquine (CQ), were extracted from blood with diethyl ether, separated and dried under nitrogen gas. Residues were reconstituted in the mobile phase and analyzed at 340 nm on a μ-bondapack C18 (250 × 4.6 mm) HPLC column with acetonitrile:methanol:KH2PO4 (10:10:80) mixture containing 0.01% triethylamine. The standard curve was linear within 50–1,500 ng/mL HCQ (R2 = 0.9996), relative errors were 1.6 to 5%, and the CV% ranged from 7 to 15.4. The resolution factor and RSD were 1.62 and 0.35% and in vitro data of both products met the USP requirements. The 90% confidence intervals for the ratios of the AUC0–96, Cmax and Tmax and their corresponding logarithmically transformed values of generic product over those of Plaquenil® were within the acceptable limit of 0.80–1.20 and 0.80–1.25, respectively. Therefore, the generic HCQ was bioequivalent to the innovator formulation.

scholarly journals Simultaneous Determination of Docetaxel and Celecoxib in Porous Microparticles and Rat Plasma by Liquid-Liquid Extraction and HPLC with UV Detection: in vitro and in vivo Validation and Application

2020 ◽  
Vol 23 ◽  
pp. 289-303
Author(s):  
Elham Ziaei ◽  
Jaber Emami ◽  
Moloud Kazemi ◽  
Mahboubeh Rezazadeh
Keyword(s):  
Internal Standard ◽  
Rat Plasma ◽  
Liquid Extraction ◽  
Uv Detection ◽  
Pharmacokinetic Studies ◽  
Liquid Liquid Extraction ◽  
Porous Microparticles ◽  
Limit Of Quantitation

Purpose: A simple, rapid, sensitive, and reliable HPLC method with UV detection was developed and validated for simultaneous quantitation of docetaxel and celecoxib and paclitaxel for dissolution characterization and pharmacokinetic studies. Methods: The HPLC assay was performed isocratically on a reversed-phase C18 μ-Bondapack column using a mobile phase of acetonitrile:water (45:55, v/v) at a flow rate of 1.2 mL/min, and the analytes were detected at 230 nm. Paclitaxel was used as an internal standard for analysis of plasma samples following simple liquid-liquid extraction with n-hexane:isoamyl alcohol (97:3). The method was validated for specificity, linearity, sensitivity, precision, accuracy, robustness, and in vitro-in vivo application. Results: The retention times for docetaxel, paclitaxel, and celecoxib were 10.94, 12.4, and 16.81 min, respectively. The standard curves covering 0.1-1 μg/mL and 0.05-4 μg/mL were linear using dissolution medium and rat plasma, respectively. The limit of quantitation of the method was 50 ng/mL using 100 μL of rat plasma sample and injection of 50 μL of the residue. Within- and between-day precision and accuracy did not exceed 16.86% and 12.10%, respectively. This validated method was successfully used to quantify docetaxel and celecoxib simultaneously in the release study of docetaxel-celecoxib -loaded porous microparticles and pharmacokinetics studies. The methods were found to be simple, specific, precise, accurate, and reproducible. In this study, paclitaxel was used as the internal standard while dexamethasone, flutamide, and budesonide proved suitable alternative as an internal standard. Conclusion: Since docetaxel and celecoxib could be co-administered for the treatment of a wide range of cancers such as non-small cell lung carcinoma, the developed method is particularly advantageous for routine therapeutic drug monitoring and pharmacokinetic studies of these drugs.

scholarly journals BIOANALYTICAL METHOD DEVELOPMENT AND VALIDATION FOR THE DETERMINATION OF SOFOSBUVIR FROM HUMAN PLASMA

2017 ◽  
Vol 9 (3) ◽  
pp. 35 ◽  
Author(s):  
S. Madhavi ◽  
A. Prameela Rani
Keyword(s):  
Human Plasma ◽  
Method Development ◽  
Quantitative Estimation ◽  
Internal Standard ◽  
Hplc Method ◽  
Array Detector ◽  
Therapeutic Drug ◽  
Specificity And Sensitivity ◽  
Photodiode Array Detector ◽  
Development And Validation

Objective: This study points to build up and validate a simple methodology to quantify the most used drug sofosbuvir for the treatment of hepatitis C virus (HCV) infection, in human plasma by using atazanavir as an Internal Standard (IS) for preclinical studies and validate as per USFDA guidelines.Methods: Sofosbuvir was isolated from plasma samples by liquid-liquid extraction method using acetonitrile; good chromatographic separation was achieved on Kromasil Column (250 mm ×4.6 mm, 5 µm). The mobile phase consisted of 0.1 % orthophosphoric acid (OPA) buffer pH 2 and acetonitrile in the ratio of (68:32, v/v), respectively. The analysis time was 7 min at a flow rate 1 ml/min. The photodiode array detector (PDA) detection was carried out at 228 nm. The suggested method was validated by performing linearity, system suitability, specificity and sensitivity, accuracy and precision, recovery, ruggedness, stability studies. The method was validated as per USFDA guidelines.Results: The developed method resulted in retention times of sofosbuvir and IS were found out to be 4.7 and 4.2 min respectively. The calibration curves are linear (r2 = 0.999) over the concentration range of 0.050-2.0 µg/ml of plasma analytes concentration. LOQ value was found to be 0.050 µg/ml with precision and accuracy. Within-batch % mean accuracy of the method ranged between 96.00% and 109.09%, and within-batch and total precision, expressed as the coefficient of variation, was 1.40–10.33%. Overall percentage mean recovery of sofosbuvir from spiked plasma was 84.14%. All the validated parameters were found to be within the limit.Conclusion: A simple, accurate, precise, linear, rugged and rapid RP-HPLC method was developed for quantitative estimation of sofosbuvir in human plasma and should be suitable for conducting pharmacokinetics studies and therapeutic drug monitoring.

scholarly journals A METHOD FOR DETERMINING 1,4-BENZOTHIAZINE DERIVATIVES IN RAT PLASMA BY HPLC AND ITS APPLICATION TO A PHARMACOKINETIC STUDY

2017 ◽  
Vol 9 (12) ◽  
pp. 82 ◽  
Author(s):  
Amit Rai ◽  
Vinit Raj ◽  
Ashok K. Singh ◽  
Amit K. Keshari ◽  
Sudipta Saha
Keyword(s):  
Pharmacokinetic Study ◽  
High Performance ◽  
Gradient Elution ◽  
Rat Plasma ◽  
Hplc Method ◽  
Array Detector ◽  
Hplc Separation ◽  
Rp Hplc ◽  
Photodiode Array Detector ◽  
Photodiode Array

Objective: The objective of the study was to develop, optimize and validate of a new reverse-phase high-performance liquid chromatography (RP-HPLC) method for the determining 1,4-benzothiazine derivatives (AR13 and AR15) in a biological sample of rat plasma. The 1,4-benzothiazine derivatives are produced by the synthetic reactions.Methods: RP-HPLC separation was performed using an ODS-2 Hypersil column with gradient elution mobile phase consisting of water-acetonitrile for AR13 and AR15 (1:9 v/v, 3:7 v/v) at room temperature 1 ml/min flow rate, and interfaced with photodiode array detector (PDA) detector, 233 nm, 235 nm respectively.Results: A linear response was obtained between (range from 0.100-10.00 mg/ml) AR13 and (range from 0.096–9.88 mg/ml) AR15 with correlation coefficient 0.999 and 0.998. The linearity range of both AR13 and AR15 was 101.65±1.5 and 98.78±1.7.Conclusion: It was concluded that the method was simple, accurate, sensitive, accurate and reproducible and has been successfully applied to the pharmacokinetic study of AR13 and AR15 in rat plasma.

Anti-thrombotic Effect of a PAI-1 Inhibitor in Rats Given Endotoxin

1996 ◽  
Vol 75 (01) ◽  
pp. 118-126 ◽  
Author(s):  
T Abrahamsson ◽  
V Nerme ◽  
M Strömqvist ◽  
B Åkerblom ◽  
A Legnehed ◽  
...  
Keyword(s):  
Plasminogen Activator Inhibitor ◽  
Rat Plasma ◽  
Clot Lysis ◽  
Fibrin Deposition ◽  
Plasminogen Activator Inhibitor 1 ◽  
Fab Fragment ◽  
Dose Dependent Decrease ◽  
Pai 1

SummaryThe aim of this study was to investigate the anti-thrombotic effects of an inhibitor of the plasminogen activator inhibitor-1 (PAI-1) in rats given endotoxin. In studies in vitro, PRAP-1, a Fab-fragment of a polyclonal antibody against human PAI-1, was shown to inhibit PAI-1 activity in rat plasma as well as to stimulate clot-lysis of the euglobulin fraction derived from rat plasma. Endotoxin administered to anaesthetised rats produced a marked increase in plasma PAI-1 activity. To study fibrin formation and lysis in vivo after intravenous (i. v.) injection of the coagulant enzyme batroxobin, 125I-fibrinogen was administered to the animals. The thrombi formed by batroxobin were rapidly lysed in control animals, while the rate of lysis was markedly attenuated in rats given endotoxin. PRAP-1 was administered i.v. (bolus + infusion) to rats given endotoxin and batroxobin and the PAI-1 inhibitor caused a dose-dependent decrease in the 125I-fibrin deposition in the lungs. An immunohistochemical technique was used to confirm this decrease in density of fibrin clots in the tissue. Furthermore, PRAP-1 decreased plasma PAI-1 activity in the rats and this reduction was correlated to the decrease in lung 125I-fibrin deposition at the corresponding time point. It is concluded that in this experimental model the PAI-1 antibody PRAP-1 may indeed inhibit thrombosis in animals exposed to endotoxin.

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