Browsing by Subject "Pharmacokinetics"
Now showing 1 - 10 of 10
Results Per Page
Sort Options
Item A pharmacokinetic study of p, p'-DDT and its metaolites during flight of the White-crowned sparrow, Zonotrichia leucophrys(Texas Tech University, 2003-12) Scollon, Edward JHistorical use of DDT has led to the bioaccumulation of DDT and its metabolites in wildlife. Avian species have proven to be particularly susceptible. DDE-induced eggshell thinning has resulted in dramatic declines of many top-level predators such as the bald eagle, peregrine falcon, and brown pelican. Despite this drawback, DDT effectively controls vector-borne diseases carriers. Therefore, its use has continued in many tropical regions. Migratory birds can bioaccumulate DDT and other lipophilic compounds in their overwintering grounds in these tropical regions, especially prior to migration when their lipid reserves are greatest. Therefore, there is a need to understand the metabolism and disposition of DDT during a migratory flight. This study was conducted to evaluate the interactions of flight, fasting, andp.p'-DDT loading on thyroid hormones, corticosterone, and residue metabolism and distribution in recently exposed white-crowned sparrows. Female sparrows were captured near Lubbock, Texas, and dosed with 5 mg p,p'- DDT per kg body weight over 3 d. Following 1 d of recovery, the sparrows were flown in a wind tunnel for up to 140 min in 15 min blocks. Food was withheld from the start of the flight period until the birds were euthanized. Consequently, birds which flew for 140 min fasted for up to 9 h. Control and fasting groups allowed measurement of hormone fluctuations and DDT metabolism not associated with DDT loading or flight. In the flown birds, corticosterone was elevated and T4 was depressed. Mean concentrations of T3 did not differ among any of the test groups. However, T3 and T4 plasma concentrations decreased over time in the flown and fasted groups. T4 decreased significantly in flown birds dosed with DDT, and T3 decreased significantly in the fasted birds dosed with DDT. DDT, DDD, and DDE were present in all of the tissues examined. DDMU, DDNU, and DDOH were not found. Fasting for up to 10 h did not significantly affect the rate of residue increase over time in any of tissues examined. When sparrows flew and fasted simultaneously, fasting still did not significantly contribute to an increase in tissue residues. However, the length of time flown was significantly correlated with increasing concentrations of DDT and DDD in the brain and DDT, DDD, and DDE in the kidney, effectively demonstrating the potential for brief flights to enhance the mobilization of DDT and its metabolites.Item Alkylmaltoside mediated nasal delivery of low molecular weight Heparin: In vitro and in vivo evaluations(Texas Tech University, 2004-05) Mustafa, FatimaThis study is designed to test the hypothesis that alkylmaltosides could be used as efficacious absorption enhancers for nasal delivery of enoxaparin, a low molecular weight heparin. The efficacy of the absorption enhancers was studied by monitoring the changes in plasma anti-factor Xa level after nasal administration of enoxaparin into anesthetized rats. In vivo reversibility study was performed to determine if the effect of the absorption enhancers on nasal membrane is reversible after acute administration of the formulations. Enoxaparin was formulated with alkylmaltosides containing varying alkyl chain lengths (octyl-, decyl-, dodecyl,- and tetradecyl-maltoside) in order to assess the role of hydrophobic chain length on the potency of the absorption enhancers. The mechanisms by which alkylmaltosides enhance permeation of enoxaparin across epithelial cells were investigated by studying the transport of radiolabelled enoxaparin and mannitol across human bronchial epithelial cells. In vitro cytotoxicity and transepithelial electric resistance recovery studies were performed to further assess the toxicity of the agents on epithelial cells. The results demonstrate that alkylmaltosides enhance enoxaparin absorption in a chain length and dose dependent manner. Of the alkylmaltosides tested, tetradecylmaltoside was most efficacious in enhancing nasal absorption of enoxaparin. It was found that the effect of octylmaltoside on nasal membrane diminishes with time and nasal mucosa re-establishes normal physiological barrier to drug absorption. Permeabilities of enoxaparin and mannitol increase in the presence of alkylmaltosides, suggesting that alkylmaftosides enhance nasal absorption of LMWH via paracellular route. Cytotoxicity studies revealed that octylmaltoside is the least toxic to the bronchial epithelial cells. Overall, the results suggest that nasal enoxaparin formulated v/ith alkylmaltosides could be a feasible alternative to subcutaneous enoxaparin.Item Biopharmaceutical classification and development of limonene-based self-nanoemulsified capsule dosage form of coenzyme Q10(Texas Tech University, 2004-05) Palamakula, AnithaCoenzyme QIO (CoQ) is a challenging micronutrient for oral formulation due to its low aqueous solubility and bioavailability. The present dissertation deals with a systematic approach to classify CoQ biopharmaceutically according to FDA biopharmaceutical classification system (BCS), and to develop a self-nanoemulsified capsule dosage form (SNCDF) with chiral limonenes. We have hypothesized that the oral bioavailability of CoQ may be enhanced by limonene based SNCDF. In vitro transport studies using Caco-2 cells and solubility studies indicated that CoQ is moderately permeable and has low solubility. However, CoQ exhibits substantial solubility in limonenes. The permeability of CoQ across isolated rat GI segments revealed regional differences with maximum absorption through duodenum. Based on these results, a limonene based self-nanoemulsified formulation of CoQ was prepared and evaluated by in vitro and in vivo methods. Dissolution studies in water have shown CoQ release of > 90% within 5 minutes. Thermal analysis showed no significant change in CoQ endotherm. FT-IR and X-ray diffraction studies revealed the preservation of CoQ structure, indicating no interactions. Particle size, turbidity and zeta potential measurements have indicated that R-(+)-limonene provided superior self-nanoemulsified formulation of CoQ when compared with S-(-)-limonene. A three-factor, three-level optimization design was used to evaluate the effect of critical process variables on the drug release characteristics. Mathematical relationships, contour plots and response surface methodology were employed with constrained optimization to predict levels of factors that provide maximum drug release. The predicted and observed responses were in good agreement. The long term stability of the formulation was ascertained by subjecting to various temperature and humidity conditions for 6 months. The results indicated no significant effect on turbidity, particle size, zeta potential, DSC, FT-IR and total drug release at room temperature. The in vivo performance of CoQ limonene based SNCDF and eutectic based self-nanoemulsified drug delivery systems (SNEDDS) was evaluated by assessing the pharmacokinetic parameters, Tmax, Cmax, and AUC in rats. The oral bioavailability of SNCDF and SNEDDS was found to increase by 650% and 730% respectively when compared with CoQ powder (control). Preliminary assessment in human volunteers indicated increased tendency of rate and extent and metabolism of nanoemulsified preparations as compared to control.Item The development of an interactive simulation for pharmacokinetics learning(2011-08) Li, Yin, master of arts in curriculum and instruction; Liu, Min, Ed. D.; Hughes, JoanThis report accounts the experience of a faculty member’s intention of creating an innovative interactive learning simulation in the field of pharmacokinetics to support the faculty member’s teaching and addresses his students’ learning needs. The report also describes the collaboration process between the faculty member and the instructional technology support units through the different phases of design, development, implementation and assessment on the simulation. It also discusses a faculty member’s role in using technology to enhance teaching and learning under university context.Item Impacts of Size on Pharmacokinetics and Biodistributions of Mebendazole Nanoformulations in Mice and Rats(2010-04-15T18:45:18Z) Qi, YulanMebendazole (Mbz), a poorly water-soluble anthelminthic drug, possesses siginificant antineoplastic effects in both in vitro and in vivo studies. Microemulsions (PM1 37nm and PM2 478 nm) and nanosuspensions (NS-167nm, NS-400nm, NS-700nm and NS-1700nm) of various sizes, and a cosolvent formulation have been developed for the potential parenteral delivery of Mbz. The purpose of the study was to investigate the role of physical nature and particle size of the nanoformulations on Mbz dispositions by comparatively establishing their pharmacokinetics and biodistribution profiles in athymic nude mouse and rat models. In vitro release studies of Mbz from the cosolvent and nanosuspensions was slower in rat plasma than in PBS, and the initial rates and extent of release from NS-167nm in PBS and rat plasma were significantly greater than those of NS-700nm and NS-1700nm in PBS, and that of NS-1700nm in rat plasma. Mbz from cosolvent and nanoformulations followed a two-compartment model after administration. PM1 and PM2 exhibited similar plasma pharmacokinetics of cosolvent in mice, with only Cmax/dose, k10 and k21 different from those of cosolvent. However, the tissue distribution patterns of PM1 and PM2 were distinct from that of cosolvent. PM1 and PM2 displayed very high AUCs/dose in lung, 6 to 7 times of that of cosolvent. The t1/2 of Mbz in lung from PM1 was longer than those of cosolvent and PM2. Different from the cosolvent, Mbz nanosuspensions exhibited very high and prolonged drug concentrations in liver and spleen due to the reticuloendothelial system (RES) uptake. The large-sized NS-1700nm displayed larger Vss and V2 (1.45 and 1.35 L) than NS-167nm (0.85 and 0.79 L) in mice. Biodistributions of Mbz from cosolvent, NS-167nm, NS-400nm, NS-700nm, and NS-1700nm in rats were comparatively established. The patterns of nanosuspensions in rats were similar to those in mice. The half-life of total Mbz in liver for NS-700nm was longer than those for NS-167nm and NS-400nm. The half-life of total Mbz in spleen for NS-400nm was longer than that for NS-167nm. The elimination half-lives of parent Mbz in liver and spleen of rats increased as particle size increased. Three-compartment pharmacokinetic models described the relationship between plasma and lung concentrations of Mbz after i.v. administration of PM1 and PM2 was successfully developed and validated, enabling the prediction of lung concentration profiles based on measured plasma concentrations. Human plasma pharmacokinetic parameters (CL, Vss, t1/2, α, and t1/2, β) for Mbz cosolvent, PM1 and PM2, as well as NS-167nm and NS-1700nm were predicted by allometric scaling. The PK parameters predicted for human from Mbz microemulsions of various sizes between PM1 and PM2 were similar, while distinct between NS-167nm and NS-1700nm. Our results demonstrated that the droplet/particle size of the nanoformulations had profound effects on Mbz dispositions in mice and rats, that might be critical in optimizing cancer therapy.Item Improved inhalation therapies of brittle powders(2013-12) Carvalho, Simone Raffa; Williams, Robert O., 1956-Advancements in pulmonary drug delivery technologies have improved the use of dry powder inhalation therapy to treat respiratory and systemic diseases. Despite remarkable improvements in the development of dry powder inhaler devices (DPIs) and formulations in the last few years, an optimized DPI system has yet to be developed. In this work, we hypothesize that Thin Film Freezing (TFF) is a suitable technology to improve inhalation therapies to treat lung and systemic malignancies due to its ability to produce brittle powder with optimal aerodynamic properties. Also, we developed a performance verification test (PVT) for the Next Generation Cascade Impactor (NGI), which is one of the most important in vitro characterization methods to test inhalation. In the first study, we used TFF technology to produce amorphous and brittle particles of rapamycin, and compared the in vivo behavior by the pharmacokinetic profiles, to its crystalline counterpart when delivered to the lungs of rats via inhalation. It was found that TFF rapamycin presented higher in vivo systemic bioavailability than the crystalline formulation. Subsequently, we investigated the use of TFF technology to produce triple fixed dose therapy using formoterol fumarate, tiotropium bromide and budesonide as therapeutic drugs. We investigated applications of this technology to powder properties and in vitro aerosol performance with respect to single and combination therapy. As a result, the brittle TFF powders presented superior properties than the physical mixture of micronized crystalline powders, such as excellent particle distribution homogeneity after in vitro aerosolization. Lastly, we developed a PVT for the NGI that may be applicable to other cascade impactors, by investigating the use of a standardized pressurized metered dose inhaler (pMDI) with the NGI. Two standardized formulations were developed. Formulations were analyzed for repeatability and robustness, and found not to demonstrate significant differences in plate deposition using a single NGI apparatus. Variable conditions were introduced to the NGI to mimic operator and equipment failure. Introduction of the variable conditions to the NGI was found to significantly adjust the deposition patterns of the standardized formulations, suggesting that their use as a PVT could be useful and that further investigation is warranted.Item Inhaled voriconazole formulations for invasive fungal infections in the lungs(2011-12) Beinborn, Nicole Angela; Williams, Robert O., 1956-Attention has begun to focus on the pulmonary delivery of antifungal agents for invasive fungal infections as inhalation of the fungal spores is often the initial step in the pathogenesis of many of these infections. Invasive fungal infection in the lungs in immunocompromised patients has high mortality rates despite current systemic (oral or intravenous) therapies. However, drug delivery of antifungal agents directly to the lungs could potentially result in high concentrations of drug in the lungs, a quicker onset of action, and reduction of systemic side effects. Voriconazole (VRC) is a second, generation triazole antifungal agent with increased potency, a broad spectrum of antifungal activity, and a fairly poor aqueous solubility. It is the recommended therapeutic agent for the treatment of Invasive Pulmonary Aspergillosis (IPA), and its use has improved therapeutic outcomes in immunocompromised patients with IPA. Still, systemic administration by oral or intravenous delivery is limited by high inter- and intra-patient pharmacokinetic variability, many potential drug interactions, and a narrow therapeutic index with many adverse effects, leading to clinical failures. Therefore, development of novel particulate formulations containing VRC for targeted drug delivery to the lungs is critical to improving therapeutic outcomes in patients with invasive fungal infections in the lungs. Within the framework of this dissertation, two particle engineering processes, thin film freezing (TFF) and advanced evaporative precipitation into aqueous solution (AEPAS), were investigated. The goal was to investigate microcrystalline VRC, nanocrystalline VRC, and nanostructured amorphous VRC formulations suitable for pulmonary delivery and to determine the effect of morphology on the in vivo deposition and distribution of inhaled particulate VRC formulations. TFF process parameters significantly affected the solid state properties and aerodynamic performance of the dry powder formulations containing VRC. Following dry powder insufflation into the lungs of mice, microstructured crystalline TFF-VRC achieved higher and more prolonged concentrations of VRC in the lungs with slightly lower systemic bioavailability than nanostructured amorphous TFF-VRC-PVP K25. AEPAS and TFF of template nanoemulsions did not lead to production of crystalline nanoparticles, as predicted. In particular, VRC proved to be a difficult molecule to stabilize in the nanocrystalline and nanostructured amorphous states. Ultimately, this body of work demonstrated that the particle engineering process, TFF, could be used to develop voriconazole formulations suitable for dry powder inhalation with more favorable pharmacokinetic parameters compared to inhaled voriconazole solution.Item Pharmacokinetics and cytoprotective evaluation of Caffeic Acid Phenethyl Amide and fluorinated derivatives against oxidative stress(2012-12) Yang, John; Stavchansky, Salomon; Bowman, Phillip D; Kerwin, Sean M; Williams, Robert O; McGinity, James WIschemic injury occurs when the flow of blood is reduced or blocked to an area of the body and can cause significant tissue damage by generation of reactive oxygen species (ROS), activation of apoptotic pathways and through induction of the inflammatory response. Restoration of blood flow and reperfusion of the blocked site, while essential, can generate a second injury that itself needs to be controlled. Together the two injuries are termed ischemia/reperfusion (I/R) injury. This type of injury is frequently encountered in medicine and is a major medical problem. Therapeutic strategies to combat I/R injury include the introduction of compounds that can scavenge ROS or can induce metabolic pathways with the effect of inhibiting apoptosis. Caffeic Acid Phenethyl Ester (CAPE), a polyphenolic compound found in propolis, has been shown to protect a variety of cells types against ROS in vitro and has also been shown to induce a variety of genes including hemeoxygenase 1 (HMOX-1) , an enzyme that has been implicated in a cytoprotective pathway. Despite showing significant cytoprotection of cells against oxidant stress in vitro, CAPE is readily hydrolyzed in plasma and is also quickly removed from circulation. This result may explain the limited cytoprotective effects of CAPE in vivo. We have synthesized a series of CAPE amide derivatives, including Caffeic Acid Phenethyl Amide (CAPA), with the aim of improving CAPE’s stability properties while maintaining the cytoprotective effects of the parent compound. We found that CAPA, in addition to 2 other amide derivatives, were able to protect human umbilical vein endothelial cells (HUVEC) against ROS to a similar degree as CAPE. In addition, we have observed significant improvement in plasma stability of CAPA over CAPE at multiple temperatures. The elimination half-life of CAPA from the systemic circulation was also seen to be significantly improved over CAPE following intravenous administration to male Sprague-Dawley rats. The longer residence time of CAPA over CAPE in circulation may potentially result in greater cytoprotection in vivo.Item Preparation and characterization of microparticulate systems for oral delivery of genistein(Texas Tech University, 2003-12) Motlekar, NusratGenistein, a potential anticancer agent was chosen as a model for poorly water-soluble drugs with low oral bioavailability. The study is based on the hypothesis that encapsulation of genistein in water soluble polymers (e.g. Polyethylene glycol) will enhance its dissolution rate. The objective of the study was to prepare, characterize, and optimize the fast release formulations- microspheres and simple dispersions. In order to achieve this goal, solid dispersions were prepared using two different techniques; solution-solvent evaporation and emulsion-solvent evaporation. Various process parameters such as ratio of drug/polymer, ratio of solvents, and speed of homogenization have been studied. A Box-Behnken experimental design was used for the preparations of simple dispersions by solution-solvent method. The formulations were compared in order to elucidate the effect of preparation methodology. Dissolution studies were performed on the formulations. Further, the solid dispersion systems were characterized using various techniques such as Differential Scanning Calorimetry, ATR-FTIR spectroscopy, in vitro dissolution, and Scanning Electron Microscopy in order to understand the physicochemical properties of the formulations. Dissolution studies showed an increase in the dissolution rate of genistein formulated as dispersion or microspheres as compared to genistein alone. Approximately, up to 5-fold enhancement in the dissolution of genistein could be achieved with the solution based formulation while up to 10-fold enhancement was observed in case of the emulsion based formulation.Item Selective targeting of the anti-viral agent lamivudine to the liver(2007-08) Chimalakonda, Krishna Chaitanya; Mehvar, Reza; Bickel, Ulrich; Klein, JochenLamivudine (3TC) is a negative enantiomer of 2’-deoxy-3’-thiacytidine, which is used in the treatment of hepatitis B virus (HBV) infection. It is desirable to selectively deliver the antiviral drugs used in the treatment of HBV infection to their site of action (liver). In this study, a liver-selective dextran prodrug (3TCSD) of the antiviral drug lamivudine (3TC) was developed and characterized. 3TC was coupled to dextran (~25 kDa) using a succinate linker, and the in vitro and in vivo behavior of the conjugate was studied using newly-developed size-exclusion and reversed-phase analytical methods. Synthesized 3TCSD had a purity of > 99% with a degree of substitution of 6.5 mg 3TC per 100 mg of the conjugate. Furthermore, the developed assays were precise and accurate in the concentration ranges of 0.125-20, 0.36-18, and 1-50 µg/mL for 3TC, 3TC succinate (3TCS), and 3TCSD, respectively. In vitro, the conjugate slowly released 3TC in the presence of rat liver lysosomes, whereas it was stable in the corresponding buffer. In vivo in rats, conjugation of 3TC to dextran resulted in forty- and seven-fold decreases in the clearance and volume of distribution of the drug, respectively. However, the accumulation of the conjugated 3TC in the liver was fifty-fold higher than that of the parent drug. The high accumulation of the conjugate in the liver was associated with a gradual and sustained release of 3TC in the liver. In addition to the liver, kidney was the only other organ where high concentrations of the conjugate were found. In contrast to the liver and kidneys, the concentrations of the conjugate and/or regenerated 3TC were very low or undetectable in the lungs, spleen, and heart after 3TCSD injection. These studies indicate the feasibility of the synthesis of 3TC-succinate-dextran and its potential use for the selective delivery of 3TC to the liver.