Commenced in January 2007
Frequency: Monthly
Edition: International
Paper Count: 11

Search results for: Pharmacokinetic

11 Time Dependent Biodistribution Modeling of 177Lu-DOTATOC Using Compartmental Analysis

Authors: M. Mousavi-Daramoroudi, H. Yousefnia, F. Abbasi-Davani, S. Zolghadri

Abstract:

In this study, 177Lu-DOTATOC was prepared under optimized conditions (radiochemical purity: > 99%, radionuclidic purity: > 99%). The percentage of injected dose per gram (%ID/g) was calculated for organs up to 168 h post injection. Compartmental model was applied to mathematical description of the drug behaviour in tissue at different times. The biodistribution data showed the significant excretion of the radioactivity from the kidneys. The adrenal and pancreas, as major expression sites for somatostatin receptor (SSTR), had significant uptake. A pharmacokinetic model of 177Lu-DOTATOC was presented by compartmental analysis which demonstrates the behavior of the complex.

Keywords: biodistribution, octreotide, compartmental modeling

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10 Optimized Preprocessing for Accurate and Efficient Bioassay Prediction with Machine Learning Algorithms

Authors: Jeff Clarine, Chang-Shyh Peng, Daisy Sang

Abstract:

Bioassay is the measurement of the potency of a chemical substance by its effect on a living animal or plant tissue. Bioassay data and chemical structures from pharmacokinetic and drug metabolism screening are mined from and housed in multiple databases. Bioassay prediction is calculated accordingly to determine further advancement. This paper proposes a four-step preprocessing of datasets for improving the bioassay predictions. The first step is instance selection in which dataset is categorized into training, testing, and validation sets. The second step is discretization that partitions the data in consideration of accuracy vs. precision. The third step is normalization where data are normalized between 0 and 1 for subsequent machine learning processing. The fourth step is feature selection where key chemical properties and attributes are generated. The streamlined results are then analyzed for the prediction of effectiveness by various machine learning algorithms including Pipeline Pilot, R, Weka, and Excel. Experiments and evaluations reveal the effectiveness of various combination of preprocessing steps and machine learning algorithms in more consistent and accurate prediction.

Keywords: Machine Learning, preprocessing, bioassay, virtual screen

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9 Formulation and in vitro Evaluation of Ondansetron Hydrochloride Matrix Transdermal Systems Using Ethyl Cellulose/Polyvinyl Pyrrolidone Polymer Blends

Authors: Rajan Rajabalaya, Li-Qun Tor, Sheba David

Abstract:

Transdermal delivery of ondansetron hydrochloride (OdHCl) can prevent the problems encountered with oral ondansetron. In previously conducted studies, effect of amount of polyvinyl pyrrolidone, permeation enhancer and casting solvent on the physicochemical properties on OdHCl were investigated. It is feasible to develop ondansetron transdermal patch by using ethyl cellulose and polyvinyl pyrrolidone with dibutyl pthalate as plasticizer, however, the desired flux is not achieved. The primary aim of this study is to use dimethyl succinate (DMS) and propylene glycol that are not incorporated in previous studies to determine their effect on the physicochemical properties of an OdHCl transdermal patch using ethyl cellulose and polyvinyl pyrrolidone. This study also investigates the effect of permeation enhancer (eugenol and phosphatidylcholine) on the release of OdHCl. The results showed that propylene glycol is a more suitable plasticizer compared to DMS in the fabrication of OdHCl transdermal patch using ethyl cellulose and polyvinyl pyrrolidone as polymers. Propylene glycol containing patch has optimum drug content, thickness, moisture content and water absorption, tensile strength, and a better release profile than DMS. Eugenol and phosphatidylcholine can increase release of OdHCl from the patches. From the physicochemical result and permeation profile, a combination of 350mg of ethyl cellulose, 150mg polyvinyl pyrrolidone, 3% of total polymer weight of eugenol, and 40% of total polymer weight of propylene glycol is the most suitable formulation to develop an OdHCl patch. OdHCl release did not increase with increasing the percentage of plasticiser. DMS 4, PG 4, DMS 9, PG 9, DMS 14, and PG 14 gave better release profiles where using 300mg: 0mg, 300mg: 100mg, and 350mg: 150mg of EC: PVP. Thus, 40% of PG or DMS appeared to be the optimum amount of plasticiser when the above combination where EC: PVP was used. It was concluded from the study that a patch formulation containing 350mg EC, 150mg PVP, 40% PG and 3% eugenol is the best transdermal matrix patch compositions for the uniform and continuous release/permeation of OdHCl over an extended period. This patch design can be used for further pharmacokinetic and pharmacodynamic studies in suitable animal models.

Keywords: eugenol, Ondansetron hydrochloride, dimethyl succinate

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8 Vincristine-Dextran Complex Loaded Solid Lipid Nanoparticles for Drug Delivery to the Brain

Authors: E. Aboutaleb, R. Dinarvand

Abstract:

The purpose of this work was to inspect the potential of vincristine-dextran complex loaded solid lipid nanoparticles for drug delivery to the brain. The nanoparticles were stained with a fluorescence dye and their plasma pharmacokinetic and brain concentrations were investigated following injection to rats. The result revealed a significant improvement in the plasma concentration profile of the SLN injected animals as well as a sharp increased concentration in the brains.

Keywords: Brain, Nanoparticles, SLN, Coumarin-6

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7 Salbutamol Sulphate-Ethylcellulose Tabletted Microcapsules: Pharmacokinetic Study using Convolution Approach

Authors: Ghulam Murtaza, Kalsoom Farzana

Abstract:

The aim of this article is to narrate the utility of novel simulation approach i.e. convolution method to predict blood concentration of drug utilizing dissolution data of salbutamol sulphate microparticulate formulations with different release patterns (1:1, 1:2 and 1:3, drug:polymer). Dissolution apparatus II USP 2007 and 900 ml double distilled water stirrd at 50 rpm was employed for dissolution analysis. From dissolution data, blood drug concentration was determined, and in return predicted blood drug concentration data was used to calculate the pharmacokinetic parameters i.e. Cmax, Tmax, and AUC. Convolution is a good biwaiver technique; however its better utility needs it application in the conditions where biorelevant dissolution media are used.

Keywords: Pharmacokinetics, Dissolution, convolution, Salbutamol sulphate

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6 Computer Modeling of Drug Distribution after Intravitreal Administration

Authors: N. Haghjou, M. J. Abdekhodaie, Y. L. Cheng, M. Saadatmand

Abstract:

Intravitreal injection (IVI) is the most common treatment for eye posterior segment diseases such as endopthalmitis, retinitis, age-related macular degeneration, diabetic retinopathy, uveitis, and retinal detachment. Most of the drugs used to treat vitreoretinal diseases, have a narrow concentration range in which they are effective, and may be toxic at higher concentrations. Therefore, it is critical to know the drug distribution within the eye following intravitreal injection. Having knowledge of drug distribution, ophthalmologists can decide on drug injection frequency while minimizing damage to tissues. The goal of this study was to develop a computer model to predict intraocular concentrations and pharmacokinetics of intravitreally injected drugs. A finite volume model was created to predict distribution of two drugs with different physiochemical properties in the rabbit eye. The model parameters were obtained from literature review. To validate this numeric model, the in vivo data of spatial concentration profile from the lens to the retina were compared with the numeric data. The difference was less than 5% between the numerical and experimental data. This validation provides strong support for the numerical methodology and associated assumptions of the current study.

Keywords: Modelling, finite volume method, pharmacokinetic, Posterior segment, Intravitreal injection (IVI)

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5 Validation and Application of a New Optimized RP-HPLC-Fluorescent Detection Method for Norfloxacin

Authors: Mahmood Ahmad, Ghulam Murtaza, Sonia Khiljee, Muhammad Asadullah Madni

Abstract:

A new reverse phase-high performance liquid chromatography (RP-HPLC) method with fluorescent detector (FLD) was developed and optimized for Norfloxacin determination in human plasma. Mobile phase specifications, extraction method and excitation and emission wavelengths were varied for optimization. HPLC system contained a reverse phase C18 (5 μm, 4.6 mm×150 mm) column with FLD operated at excitation 330 nm and emission 440 nm. The optimized mobile phase consisted of 14% acetonitrile in buffer solution. The aqueous phase was prepared by mixing 2g of citric acid, 2g sodium acetate and 1 ml of triethylamine in 1 L of Milli-Q water was run at a flow rate of 1.2 mL/min. The standard curve was linear for the range tested (0.156–20 μg/mL) and the coefficient of determination was 0.9978. Aceclofenac sodium was used as internal standard. A detection limit of 0.078 μg/mL was achieved. Run time was set at 10 minutes because retention time of norfloxacin was 0.99 min. which shows the rapidness of this method of analysis. The present assay showed good accuracy, precision and sensitivity for Norfloxacin determination in human plasma with a new internal standard and can be applied pharmacokinetic evaluation of Norfloxacin tablets after oral administration in human.

Keywords: RP-HPLC method, norfloxacin, Aceclofenac sodium, Methodoptimization, Fluorescent detection, Calibrationcurve

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4 Three Computational Mathematics Techniques: Comparative Determination of Area under Curve

Authors: Khalid Pervaiz Akhter, Mahmood Ahmad, Ghulam Murtaza, Ishrat Shafi, Zafar Javed

Abstract:

The objective of this manuscript is to find area under the plasma concentration- time curve (AUC) for multiple doses of salbutamol sulphate sustained release tablets (Ventolin® oral tablets SR 8 mg, GSK, Pakistan) in the group of 18 healthy adults by using computational mathematics techniques. Following the administration of 4 doses of Ventolin® tablets 12 hourly to 24 healthy human subjects and bioanalysis of obtained plasma samples, plasma drug concentration-time profile was constructed. AUC, an important pharmacokinetic parameter, was measured using integrated equation of multiple oral dose regimens. The approximated AUC was also calculated by using computational mathematics techniques such as repeated rectangular, repeated trapezium and repeated Simpson's rule and compared with exact value of AUC calculated by using integrated equation of multiple oral dose regimens to find best computational mathematics method that gives AUC values closest to exact. The exact values of AUC for four consecutive doses of Ventolin® oral tablets were 150.5819473, 157.8131756, 164.4178231 and 162.78 ng.h/ml while the closest values approximated AUC values were 149.245962, 157.336171, 164.2585768 and 162.289224 ng.h/ml, respectively as found by repeated rectangular rule. The errors in the approximated values of AUC were negligible. It is concluded that all computational tools approximated values of AUC accurately but the repeated rectangular rule gives slightly better approximated values of AUC as compared to repeated trapezium and repeated Simpson's rules.

Keywords: Salbutamol sulphate, Area under curve (AUC), repeated rectangular rule, repeated trapezium rule, repeated Simpson's rule

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3 New Simultaneous High Performance Liquid Chromatographic Method for Determination of NSAIDs and Opioid Analgesics in Advanced Drug Delivery Systems and Human Plasma

Authors: Asad Ullah Madni, Mahmood Ahmad, Naveed Akhtar, Muhammad Usman

Abstract:

A new and cost effective RP-HPLC method was developed and validated for simultaneous analysis of non steroidal anti inflammatory dugs Diclofenac sodium (DFS), Flurbiprofen (FLP) and an opioid analgesic Tramadol (TMD) in advanced drug delivery systems (Liposome and Microcapsules), marketed brands and human plasma. Isocratic system was employed for the flow of mobile phase consisting of 10 mM sodium dihydrogen phosphate buffer and acetonitrile in molar ratio of 67: 33 with adjusted pH of 3.2. The stationary phase was hypersil ODS column (C18, 250×4.6 mm i.d., 5 μm) with controlled temperature of 30 C°. DFS in liposomes, microcapsules and marketed drug products was determined in range of 99.76-99.84%. FLP and TMD in microcapsules and brands formulation were 99.78 - 99.94 % and 99.80 - 99.82 %, respectively. Single step liquid-liquid extraction procedure using combination of acetonitrile and trichloroacetic acid (TCA) as protein precipitating agent was employed. The detection limits (at S/N ratio 3) of quality control solutions and plasma samples were 10, 20, and 20 ng/ml for DFS, FLP and TMD, respectively. The Assay was acceptable in linear dynamic range. All other validation parameters were found in limits of FDA and ICH method validation guidelines. The proposed method is sensitive, accurate and precise and could be applicable for routine analysis in pharmaceutical industry as well as in human plasma samples for bioequivalence and pharmacokinetics studies.

Keywords: Validation, tramadol, Flurbiprofen, diclofenac sodium, HPLCUV detection

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2 The Effect of Loperamide and Fentanyl on the Distribution Kinetics of Verapamil in the Lung and Brain in Sprague Dawley Rats

Authors: Iman A. Elkiweri, Ph.D, Martha C. Tissot van Patot, Ph.D., Yan Ling Zhang, Ph.D., Uwe Christians, Ph.D., Thomas K. Henthorn, M.D.,

Abstract:

Verapamil has been shown to inhibit fentanyl uptake in vitro and is a potent P-glycoprotein inhibitor. Tissue partitioning of loperamide, a commercially available opioid, is closely controlled by the P-gp efflux transporter. The following studies were designed to evaluate the effect of opioids on verapamil partitioning in the lung and brain, in vivo. Opioid (fentanyl or loperamide) was administered by intravenous infusion to Sprague Dawley rats alone or in combination with verapamil and plasma, with lung and brain tissues were collected at 1, 5, 6, 8, 10 and 60 minutes. Drug dispositions were modeled by recirculatory pharmacokinetic models. Fentanyl slightly increased the verapamil lung (PL) partition coefficient yet decreased the brain (PB) partition coefficient. Furthermore, loperamide significantly increased PLand PB. Fentanyl reduced the verapamil volume of distribution (V1) and verapamil elimination clearance (ClE). Fentanyl decreased verapamil brain partitioning, yet increased verapamil lung partitioning. Also, loperamide increased lung and brain partitioning in vivo. These results suggest that verapamil and fentanyl may be substrates of an unidentified inward transporter in brain tissue and confirm that verapamil and loperamide are substrates of the efflux transporter P-gp.

Keywords: partition coefficient, Efflux transporter, elimination clearance, verapamil

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1 Bridging the Mental Gap between Convolution Approach and Compartmental Modeling in Functional Imaging: Typical Embedding of an Open Two-Compartment Model into the Systems Theory Approach of Indicator Dilution Theory

Authors: Gesine Hellwig

Abstract:

Functional imaging procedures for the non-invasive assessment of tissue microcirculation are highly requested, but require a mathematical approach describing the trans- and intercapillary passage of tracer particles. Up to now, two theoretical, for the moment different concepts have been established for tracer kinetic modeling of contrast agent transport in tissues: pharmacokinetic compartment models, which are usually written as coupled differential equations, and the indicator dilution theory, which can be generalized in accordance with the theory of lineartime- invariant (LTI) systems by using a convolution approach. Based on mathematical considerations, it can be shown that also in the case of an open two-compartment model well-known from functional imaging, the concentration-time course in tissue is given by a convolution, which allows a separation of the arterial input function from a system function being the impulse response function, summarizing the available information on tissue microcirculation. Due to this reason, it is possible to integrate the open two-compartment model into the system-theoretic concept of indicator dilution theory (IDT) and thus results known from IDT remain valid for the compartment approach. According to the long number of applications of compartmental analysis, even for a more general context similar solutions of the so-called forward problem can already be found in the extensively available appropriate literature of the seventies and early eighties. Nevertheless, to this day, within the field of biomedical imaging – not from the mathematical point of view – there seems to be a trench between both approaches, which the author would like to get over by exemplary analysis of the well-known model.

Keywords: Functional Imaging, Tracer kinetic modeling, LTIsystem, Indicator dilution theory / convolution approach, Two-Compartment model

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