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David Stepensky
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ABSTRACT: INTRODUCTION: Drug distribution is a major pharmacokinetic process that affects the time course of drug concentrations in tissues, biological fluids and the resulting pharmacological activities. Drug distribution may follow different pathways and patterns, and is governed by the drug's physicochemical properties and the body's physiology. The classical Øie-Tozer model is frequently used for predicting volume of drug distribution and for pharmacokinetic calculations. AREAS COVERED: In this review, the suitability of the Øie-Tozer model for drugs that exhibit different distribution patterns is critically analyzed and illustrated. The method used is a pharmacokinetic modeling and simulation approach. It is demonstrated that the major limitation of the Øie-Tozer model stems from its focus on the total drug concentrations and not on the active (unbound) concentrations. Moreover, the Øie-Tozer model may be inappropriate for drugs with nonlinear or complex pharmacokinetic behavior, such as biopharmaceuticals, drug conjugates or for drugs incorporated into drug delivery systems. Distribution mechanisms and alternative distribution models for these drugs are discussed. EXPERT OPINION: The Øie-Tozer model can serve for predicting unbound volume of drug distribution for 'classical' small molecular mass drugs with linear pharmacokinetics. However, more detailed mechanism-based distribution models should be used in preclinical and clinical settings for drugs that exhibit more complex pharmacokinetic behavior.
Expert Opinion on Drug Metabolism & Toxicology 10/2011; 7(10):1233-43. · 3.12 Impact Factor
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ABSTRACT: Intracellularly targeted delivery system based on PLGA nanoparticles decorated with endoplasmic reticulum (ER)-targeting or control peptides and encapsulating antigenic peptide and fluorescent marker, was developed and characterized. The cellular uptake by dendritic cells (murine DC2.4 cells), intracellular trafficking, and cross-presentation efficiency of this delivery system were studied in vitro. The prepared nanoparticles (an average diameter of ~350 nm) efficiently encapsulated antigenic peptide and fluorescent marker and gradually released them over several days. Yet, the nanoparticles' size was small enough to allow their efficient endocytosis by the antigen-presenting cells in vitro. Surface conjugation of the targeting or control peptides enhanced the endocytosis of the nanoparticles, affected their intracellular trafficking, and induced prolonged low-magnitude cross-presentation of the antigenic peptide. We demonstrated in vitro that the intracellular fate of nanoparticulate drug delivery systems can be altered by their surface decoration with peptidic targeting residues. More detailed investigation is required to determine the mechanisms and therapeutic potential of intracellular targeting of nanodelivery systems in vivo for the goal of an anticancer vaccine.
Molecular Pharmaceutics 06/2011; 8(4):1266-75. · 4.78 Impact Factor
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ABSTRACT: Since its role in the prevention of osteoporosis in humans was proven some 30 years ago, calcium bioavailability has been the subject of numerous scientific studies. Recent technology allowing the production of a stable amorphous calcium carbonate (ACC) now enables a bioavailability analysis of this unique form of calcium. This study thus compares the solubility and fractional absorption of ACC, ACC with chitosan (ACC-C), and crystalline calcium carbonate (CCC). Solubility was evaluated by dissolving these preparations in dilute phosphoric acid. The results demonstrated that both ACC and ACC-C are more soluble than CCC. Fractional absorption was evaluated by intrinsically labeling calcium carbonate preparations with (45)Ca, orally administrated to rats using gelatin capsules. Fractional absorption was determined by evaluating the percentage of the administrated radioactive dose per milliliter that was measured in the serum, calcium absorption in the femur, and whole-body retention over a 34-hour period. Calcium serum analysis revealed that calcium absorption from ACC and ACC-C preparations was up to 40% higher than from CCC, whereas retention of ACC and ACC-C was up to 26.5% higher than CCC. Absorbed calcium in the femurs of ACC-administrated rats was 30% higher than in CCC-treated animals, whereas 15% more calcium was absorbed following ACC-C treatment than following CCC treatment. This study demonstrates the enhanced solubility and bioavailability of ACC over CCC. The use of stable ACC as a highly bioavailable dietary source for calcium is proposed based on the findings of this study.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 02/2011; 26(2):364-72. · 6.04 Impact Factor
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ABSTRACT: Efficient intracellular targeting of drugs and drug delivery systems (DDSs) is a major challenge that should be overcome to enhance the therapeutic efficiency of biopharmaceuticals and other intracellularly-acting drugs. Studies that quantitatively assess the mechanisms, barriers, and efficiency of intracellular drug delivery are required to determine the therapeutic potential of intracellular targeting of nano-delivery systems. In this study we report development and application of a novel 'IntraCell' plugin for ImageJ that is useful for quantitative assessment of uptake and intracellular localization of the drug/DDS and estimation of targeting efficiency. The developed plugin is based on threshold-based identification of borders of cell and of the individual organelles on confocal images and pixel-by-pixel analysis of fluorescence intensities. We applied the developed 'IntraCell' plugin to investigate uptake and intracellular targeting of novel endoplasmic reticulum (ER)-targeted delivery system based on PLGA nanoparticles decorated with ER-targeting or control peptides and encapsulating antigenic peptide and fluorescent marker. Decoration of the nanoparticles with peptidic residues affected their uptake and intracellular trafficking in HeLa cells, indicating that the targeting peptide was identified as ER-targeting signal by the intracellular trafficking mechanisms in HeLa cells and that these mechanisms can handle nano-DDS of the size comparable to some intracellular vesicles (hundreds of nanometers in diameter). We conclude that decoration of nanoparticles with peptidic residues affects their intracellular localization and trafficking and can be potentially used for intracellularly-targeted drug delivery. 'IntraCell' plugin is an useful tool for quantitative assessment of efficiency of uptake and intracellular drug targeting. In combination with other experimental approaches, it will be useful for the development of intracellularly-targeted formulations with enhanced and controlled drug pharmacological activities, such as delivery of antigenic peptides for anticancer vaccination and for other applications.
Biochemical and Biophysical Research Communications 02/2011; 405(2):228-33. · 2.48 Impact Factor
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David Stepensky
Pharmaceutical Research 12/2010; 27(12):2776-80. · 4.09 Impact Factor
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David Stepensky
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ABSTRACT: Volume of drug distribution is a primary pharmacokinetic parameter. This study assessed effects of drugs' plasma protein binding and tissue distribution on volume of drug distribution and identified the most appropriate ways for its calculation. Effects of the distribution factors on the unbound and total drug plasma concentrations and on the corresponding volumes of distribution were studied using pharmacokinetic modeling and simulation approach based on in vitro and in vivo concentration vs. time data of diazepam, a model drug with extensive plasma protein binding and tissue distribution. Pharmacokinetics of diazepam were appropriately described by three-compartment pharmacokinetic model that incorporated the processes of plasma protein binding and tissue permeation. According to this model, displacement of the drug from plasma proteins increases the unbound (but not the total) plasma concentrations and induces faster drug elimination from the body. The distribution pattern of the drug in the body and the time course of unbound (pharmacologically active) drug concentrations correlated with the unbound volumes of distribution, but not with the total volumes of distribution. In conclusion, unbound volumes of distribution appropriately describe the drug distribution pattern and the time course of unbound drug concentrations and are recommended for use as primary pharmacokinetic parameters in pharmaceutical research.
European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 11/2010; 42(1-2):91-8. · 2.61 Impact Factor
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ABSTRACT: To assess the corneal iontophoretic delivery of gentamicin by drug-loaded hydrogel probe, and to determine the resultant ocular disposition and elimination of the drug from the cornea and anterior chamber.
Corneal iontophoresis of gentamicin sulfate was studied in healthy white rabbits by using drug-loaded disposable hydroxyethyl methacrylate (HEMA) hydrogel disk probes and a portable mini-ion device designed in the authors' laboratory. The iontophoretic treatment was performed with a current intensity of 1 mA for 60 seconds only. Three control groups were used: mock iontophoresis (no current) for 60 seconds, topical eye drops of fortified gentamicin (1.4%) every 5 minutes for 1 hour, and subconjunctival injection of 0.25 mL of 40 mg/mL gentamicin solution. The animals in the iontophoretic experimental groups were killed at predetermined time points. The gentamicin concentrations in the cornea and aqueous humor were assayed with a fluorescence polarization immunoassay. Analysis of the gentamicin eye pharmacokinetics was performed with a modeling approach.
Peak gentamicin concentrations in the cornea (363.1 +/- 127.3 microg/g) and in the aqueous humor (29.4 +/- 17.4 microg/mL) were reached at 0 and 2 hours after the iontophoretic treatment, respectively. The peak gentamicin concentrations after a single iontophoresis treatment were 12 to 15 times higher than those obtained after gentamicin injection or after topical eye drop instillation, and much higher than in mock iontophoresis. The concentration versus time profile of gentamicin in the cornea and the anterior chamber after iontophoresis was appropriately described by applying a two-compartment pharmacokinetic model.
A short iontophoretic treatment using gentamicin-loaded hydrogels has potential clinical value in increasing drug penetration to the anterior segments of the eye and maintaining therapeutic drug levels in the cornea for more than 8 hours.
Investigative Ophthalmology & Visual Science 09/2004; 45(8):2543-8. · 3.60 Impact Factor
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ABSTRACT: Controlled release gastroretentive dosage forms (CR-GRDF) enable prolonged and continuous input of the drug to the upper parts of the gastrointestinal (GI) tract and improve the bioavailability of medications that are characterized by a narrow absorption window. CR-GRDF provide a means to utilize all the pharmacokinetic (PK) and pharmacodynamic (PD) advantages of controlled release dosage forms for such drugs. Thus, CR-GRDF may improve therapy with clinically used medications, as well as enable oral administration of drugs, or drug candidates, that hitherto had to be infused parenterally. This manuscript discusses the complexity of the PK and PD factors that influence the treatment benefits of CR-GRDF and summarizes the results of our recent in vivo investigations in animal models (rats and dogs) and in human subjects. We found that a CR-GRDF formulation was superior to the other modes of administration for levodopa and riboflavin, but not for metformin. The PK and PD rationales of GRDFs for the studied drugs are presented and discussed. We conclude that due to the complexity of the PK and PD factors for a certain drug, the rationale for continuous administration obtained by CR-GRDF should be assessed and established in vivo.
International Journal of Pharmaceutics 07/2004; 277(1-2):141-53. · 3.35 Impact Factor
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ABSTRACT: Injectable formulations of L-adrenaline are commonly used in emergency medicine. Despite numerous studies, the comparative contribution and kinetics of the L-adrenaline inactivation pathways during storage have not been conclusively evaluated. We examined the kinetics of L-adrenaline degradation in a prospective study and determined the extent of drug inactivation by different pathways during and beyond the stipulated product shelf-life in 42 batches of adrenaline ampules stored under controlled conditions. The content of L-adrenaline and degradation products was determined with a chiral high-performance liquid chromatography (HPLC) assay, and the degradation products were identified by mass spectrometric detection as D-adrenaline and L- and D-adrenaline sulfonate. The kinetics of the content change with storage was analyzed simultaneously for L-adrenaline and the degradation products using kinetic modeling. The lower acceptable level of adrenaline content in the formulation stated by US Pharmacopoeia (90% as a sum of L- and D-isomers) was attained after 2.0 years of storage, at which time the content of the therapeutically active L-isomer amounted to as low as 85%. The modeling revealed significant differences in the degradation kinetics in the formulations produced before and after 1997, whose cause remained unidentified in this study.
Journal of Pharmaceutical Sciences 05/2004; 93(4):969-80. · 3.06 Impact Factor
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ABSTRACT: The objective of this study was to evaluate the pharmacokinetic and pharmacodynamic properties of furosemide following gastroretentive dosage from (GRDF) administration. A furosemide (60 mg) GRDF, releasing the drug during 6 hours in vitro, or an immediate-release tablet was administered to healthy male volunteers (N = 14) in a crossover design. Food and liquid intake were standardized; urine was collected, weighed, and assayed for furosemide and sodium concentrations. Pharmacokinetics of furosemide following the GRDF administration, as compared to the tablet, showed lower Cmax and indicated a prolonged absorption phase leading to longer mean residence time in the stomach. The sustained input of the drug significantly improved diuretic and natriuretic efficiencies during the first 5 hours and thereby increased the total effects measured over 24 hours. The unfolding controlled-release GRDF of furosemide improved the pharmacodynamic actions due to the sustained absorption in the stomach and jejunum, which delayed the body's counteractivity to the drug effect.
The Journal of Clinical Pharmacology 08/2003; 43(7):711-20. · 2.91 Impact Factor
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ABSTRACT: "Bone-seeking agents" are drugs characterised by high affinity for bone, and are disposed in bone for prolonged periods of time while maintaining remarkably low systemic concentrations. As a consequence, the bone becomes a reservoir for bone-seeking agents, and a site of both desirable and adverse effects, depending on the pharmacological activities of the specific agent. For some agents, significant systemic effects may also be produced following their prolonged release from bone, a process that is governed mostly by the rate of bone remodelling. This review covers the pharmacokinetic and pharmacodynamic features of bone-seeking agents with different pharmacological properties, including drugs (bisphosphonates, drug-bisphosphonate conjugates, radiopharmaceuticals and fluoride), bone markers (tetracycline, bone imaging agents) and toxins (lead, chromium, aluminium). In addition, drugs that do not possess bone-seeking properties but are used for therapy of bone diseases (such as antibacterials for treatment of osteomyelitis) are discussed, along with targeting of these drugs to the bone by conjugation to bone-seeking agents, local delivery systems, and other approaches. The pharmacokinetic and pharmacodynamic behaviour of bone-seeking agents is extremely complex due to heterogeneity in bone morphology and physiology. This complexity, accompanied by difficulties in human bone research caused by ethical and other limitations, gave rise to modelling approaches to study bone drug disposition. This review describes the pharmacokinetic models that have been proposed to describe the pharmacokinetic behaviour of bone-seeking agents and predict bone concentrations of these agents for different doses and patient populations. Models of different types (compartmental and physiologically based) and of different complexity have been applied, but their relevance to drug effects in the bone tissue is limited since they describe the behaviour of the "average" drug molecule. Understanding of the cellular and molecular processes responsible for the heterogeneity of bone tissue will provide better comprehension of the influence of microenvironment on drug bone disposition and the resulting pharmacological response.
Clinical Pharmacokinetics 02/2003; 42(10):863-81. · 5.40 Impact Factor
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ABSTRACT: We used a novel pharmacokinetic-pharmacodynamic (PK-PD) approach that had been applied for signal transduction kinetics to investigate the kinetics of the parasympathomimetic effect of scopolamine and atropine in rats. The parasympathetic tone was assessed by continuous measurement of the power of the high frequency band (HF) of electrocardiogram (ECG) R-R intervals obtained by power spectral analysis (PSA) of heart rate variability (HRV). To overcome the inherent noise of the HRV-HF data and to quantitatively identify temporal changes in the autonomic tone, a new approach of stepwise regression of the cumulative HF data was applied. The elevation of the parasympathetic tone occurred after a significant lag time (>70 min) following scopolamine administrations [0.25 and 0.5 mg/kg intravenous (iv) bolus or infusion over 100 min], followed by a gradual return to the baseline levels. A similar lag time in parasympathetic stimulation was observed following iv bolus administration of atropine (0.1 mg/kg). The plasma drug concentration versus time data were linked to the response versus time data using a signal transduction pharmacodynamic model that was fitted simultaneously to all four experimental data sets. This PK-PD model resolved the significant discrepancy between the concentration versus time and the response versus time patterns and successfully described the kinetics of the parasympathetic stimulation obtained for different drugs and different rates of administration. This work paves the way for further PK-PD preclinical investigations in this field.
Journal of Pharmaceutical Sciences 12/2002; 91(12):2500-10. · 3.06 Impact Factor
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ABSTRACT: [corrected] The purpose of this study was to design novel gastroretentive dosage forms (GRDFs) based on unfolding multilayer polymeric films, to investigate the mechanism of their gastroretentivity in dogs, and to assess the effect of compounding a narrow absorption window drug in a GRDF on the drug's absorption properties.
Dosage forms (DFs) with different dimensions and mechanical properties were administered to beagle dogs with acidic buffer (pH = 1.5), whose gastric retention time (GRT) was then determined by X-ray pictures. Concurrent administration of radiopaque markers was used to assess the effect of the GRDF and/or acidic buffer on GRT. The absorption of riboflavin from a prototype GRDF was compared with a nongastroretentive controlled-release DF and to an oral solution of the drug.
Large DFs (> or = 2.5 x 2.5 cm) containing rigid frame had prolonged GRT (>4 h). Administration of 400 mL of acidic buffer (or water) prolonged GRT whereas the GRDF did not cause additional prolongation. The extended absorption phase (>48 h) of riboflavin administered in a GRDF led to 4-fold increased bioavailability.
The combination of large dimensions with rigidity produce gastroretentivity that can be used to improve absorption properties of a model of narrow absorption window drugs in the gastrointestinal tract.
Pharmaceutical Research 11/2002; 19(10):1516-23. · 4.09 Impact Factor
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ABSTRACT: Metformin, a commonly used antidiabetic drug, exerts its glucose-lowering effect due to metabolic activities at several sites of action (biophases), including liver, intestine, muscle cells, and adipocytes. The relative contribution of the individual biophases to the overall glucose-lowering effect is not known. Thus, the aims of this investigation were to study the influence of mode of drug administration on the kinetics of glucose-lowering action of metformin in diabetic rats and identify the contribution of different sites of action to the overall response. Streptozotocin diabetic rats received metformin in crossover fashion via intraduodenal, intravenous, and intraportal routes as bolus dose or infusion regimens designed to yield similar pharmacokinetic profiles. Metformin plasma concentrations and blood glucose levels were measured following each mode of administration. Despite the similarity in the concentration-time profiles obtained for different routes of metformin administration, intraduodenal administration produced larger response than intraportal metformin infusion, and lowest response was observed following intravenous administration. This finding indicates that a significant "first-pass" pharmacodynamic effect, which occurs in the presystemic sites of action (liver and the gastrointestinal wall), contributes to the overall glucose-lowering response of metformin. We applied a combined pharmacokinetic-pharmacodynamic modeling approach to study the nature of the first-pass pharmacodynamic effect. The observed data were successfully described by a novel integrated indirect response pharmacokinetic-pharmacodynamic model that revealed a correlation between the temporal metformin concentrations that transit the portal vein and through the gut wall rather than with drug concentrations that accumulated in the liver and the intestinal wall.
Drug Metabolism and Disposition 09/2002; 30(8):861-8. · 3.73 Impact Factor
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ABSTRACT: We studied the differences in pharmacokinetics and pharmacodynamics of the same dose of alendronate administered subcutaneously as intermittent bolus injection or continuous infusion in rats. Two rat models of bone disease were applied. Bone cancer was produced by intratibial inoculation of Walker carcinosarcoma cells, and a model of augmented bone resorption was produced by vitamin D(3) treatment of rats that had undergone thyroidparathyroidectomy. Higher amounts of alendronate were found in bones and in internal organs after bolus drug administration as compared with continuous infusion. Drug effects on plasma calcium levels and on urine calcium excretion were similar in both modes of alendronate administration. Results of the study indicate that the pharmacokinetics (disposition) of alendronate is administration-dependent. The total amount found in bone does not directly represent the amount of alendronate that is pharmacologically active at the site of action in the bone and that affects bone remodeling. The findings suggest that there is no pharmacodynamic advantage for continuous infusion of alendronate. It is concluded that the preferred mode of administration should be selected according to secondary clinical criteria (like incidence of adverse effects and convenience of administration).
Journal of Pharmaceutical Sciences 03/2002; 91(2):508-16. · 3.06 Impact Factor
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ABSTRACT: Purpose. To utilize power spectral analysis (PSA) of heart rate variability (HRV) as a pharmacodynamic (PD) measure of atropine parasympathetic effect, and to model the kinetics of action.
Methods. Heart rate data was collected following atropine administration to rats and was analyzed off-line for high frequency peaks by PSA of HRV as a measure of parasympathetic tone. A temporal cumulative approach (TCA) detected transient changes in parasympathetic activity. The pharmacokinetics (PK) was analyzed and linked to both direct and indirect PK-PD models.
Results. TCA enabled a quantitative measure of atropine parasympathetic activity. A simultaneous fit of the indirect PK-PD model to the experimental data of all three atropine doses successfully captured the experimental data.
Conclusions. TCA can be used as a quantitative measure of parasympathetic tone. Our work has established a preclinical model to investigate the kinetics of drug action on the autonomic nervous system.
Pharmaceutical Research 07/2001; 18(8):1220-1225. · 4.09 Impact Factor
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ABSTRACT: We investigated the influence of mode of administration on the pharmacokinetics of a clinically used bisphosphonate, pamidronate, and of suberoylbisphosphonate (SuBP), a novel bisacylphosphonate of the P–CO–(C)n–CO–P type, in rats. Serum drug levels and tissue disposition were determined following administration of the drugs by different modes: intravenous bolus (iso-osmotic and hypo-osmotic solutions), continuous intravenous infusion, and peroral administration. Results of the study indicate that the disposition of the bisphosphonates in soft tissue (liver, kidney and spleen) was dependent on route and rate of drug administration, and on the osmoticity of the vehicle. Consequently, main pharmacokinetic parameters (AUC, CL, and Vss) were influenced by the mode of drug administration, precluding accurate determination of bioavailability from AUC values. On the other hand, bone and urine bisphosphonate accumulation were considerably less dependent on mode of administration, and, therefore, are recommended for bioavailability calculation.
International Journal of Pharmaceutics.
