No description available.

MSc (Med), Faculty of Health Sciences, University of the Witwatersrand, 2010 / The poor bioavailability of drugs has been identified as the single most important challenge in oral drug delivery. Prominent among the factors responsible for this are the metabolic activity of the intestinal and hepatic cytochrome P450 enzyme family. This dissertation presents novel cytochrome P450 inhibitors generated through the application of computational modeling of known cytochrome P450-substrate and cytochrome P450-inhibitor interactions. In vitro metabolism of felodipine by cytochrome P450 3A4-expressed human liver microsomes was optimized yielding a typical Michaelis-Menten plot through the application of Enzyme Kinetic Module software from where the enzyme kinetic parameters were determined. Quercetin, naringin and naringenin which are the major phytochemical component of grapefruit juice, a well known cytochrome P450 3A4 inhibitor, were separately incubated in human liver microsomes together with felodipine at concentration equivalent to the determined Michaelis-Menten Constant (Km) value. Compared to verapamil, a known competitive inhibitor of cytochrome P450 3A4, all three flavonoids inhibited felodipine metabolism with IC50 values of 208.65, 177.81 and 121.97μM respectively confirming earlier suggestions that the flavonoid contents of grapefruit juice are responsible for known grapefruit-drug interactions. Following a detailed study of the quantitative structure-activity relationship of these flavonoids and verapamil, their binding properties with cytochrome P3A4, the amino acid sequence and binding affinity of cytochrome P3A4, computational modeling software on a non-silicon graphic system was employed to generate pharmaceutical grade and commercially available polymers based on activity prediction aided by computational biomimetism and simulations. Thus grapefruit-felodipine interaction (a typical cytochrome P3A4 inhibitor-substrate interaction) served as the basis for the computational modeling where several modeled compounds including 8-arm-poly(ethylene glycol), o-(2-aminoethyl)-o-methyl poly(ethylene glycol), 4-arm-poly(ethylene glycol) (MW=10000g/mol and 20000g/mol) and poly (L-lysine) were generated and investigated for inhibitory activity against felodipine metabolism by human liver microsomes and human intestinal microsomes where 8-arm-poly(ethylene glycol) demonstrated the highest inhibitory potency with an IC50 value of 7.22μM. An ex vivo method employing freshly excised pig intestinal tissue was developed and validated to investigate the inhibition of cytochrome P450-induced drug metabolism in living tissues. Both naringenin and 8-arm-poly(ethylene glycol) exhibited significant inhibitory effects against felodipine metabolism in pig intestinal tissues. The ex vivo studies yielding IC50 values of 179.88 and 487.75μM for naringenin and 8-arm-poly(ethylene glycol) respectively demonstrated a promising in vivo inhibitory activity against intestinal cytochrome P450 3A4. The potential utility of 8-arm-poly(ethylene glycol) in oral drug delivery was investigated by assessing its influence on the formulation and behavior of tablet matrices. Results showed that 8-arm-poly(ethylene glycol) possessed satisfactory compressional, binding and friability characteristics with acceptable drug release profiles. In vivo studies of the effects of 8-arm-poly(ethylene glycol) on the oral bioavailability of felodipine were performed on the Large White pig model. Compared to controls, a >100% increase in plasma felodipine levels was observed. The outcome of this research presents 8-arm-poly(ethelyne glycol) as a promising oral bioavailability enhancer.

University of Macau / Institute of Chinese Medical Sciences

Soil that is contaminated with radioactive elements poses an exposure hazard to those whom may take up temporary or permanent residence on such a site. Of particular interest is the internal exposure from ingestion of this radioactive soil. Although most ingestion of soil is inadvertent, usually being attached to foodstuffs that are not properly cleaned, it is possible that a person might consume a larger quantity. Childhood soil ingestion from simple hand-to-mouth activities is one explanation for this larger intake, as well as geophagia (eating dirt) or pica (craving and eating non-food items). The assumption that any person might consume a "mouthful" of dirt is a rare but possible occurrence that, when analyzed, will help with decisions about safe contamination levels of soil. Samples of soils contaminated with radium-226 were sent from an engineering and environmental firm to Oregon State University's Department of Nuclear Engineering and Radiation Health Physics for assessment. The analysis of the samples was aimed at the determination of bioavailability and bioaccessibility of the radioactive species found in the soils. Subsequent site remediation actions for the New Jersey-based project would be partially dictated by the results of Oregon State University's testing. Initially, the soils were tested for the presence of carbonates, for leachability of radioactivity in water and in acid, and for particle size distribution, i.e., soil type. Each of the eight samples was then subjected to a stomach/intestinal analogue to determine how much of the radioactivity would be transferred to solution upon human ingestion, (bioaccessibility). Mass balance and gamma spectrometry outputs for the soil samples before and after the digestion was one way the loss to solution was assessed. Another method to determine the loss of radioactivity to solution was to count aliquots of the digestive fluids in a high purity germanium detector, using a library of only radium isotopes and their progeny to locate peaks. The combination of results from mass balance and gamma spectrometry outputs allowed for OSU's researchers to determine the bioaccessibility of each soil's radioactive components. Using the determined bioaccessibility and previous animal models, the determination of bioavailability varied between the samples, from zero to 28% of the total initial radioactivity in the samples. A hot particle estimation of the dose from the non-bioavailable portion of the samples yielded a high dose to a small number of cells. Assuming ingestion of the most radioactive sample, (Sum-03a), the amount of damaged (killed) tissue in each section of the gastrointestinal tract was estimated to be less than 0.0407 cm³. This small volume of tissue is not likely to result in evident damage as the healthy human gastrointestinal tract regenerates all surface cells approximately every six days and most items are resident in the digestive system for less than 48 hours. / Graduation date: 2006

Gastrointestinal (GI) transit data were collected using pigs as animal models. Density and size effects of non-disintegrating dosage forms on GI transit were investigated. Total GI transit times range from 2 to 33 days for 22 administrations of these nondisintegrating dosage forms. Pigs are found to not be an appropriate animal model for studying bioavailability or GI transit of non-disintegrating, non-erodible oral release dosage forms. Development of controlled release dosage forms where the mechanism of drug release is diffusion through polymeric membrane formed via film coating utilizing fluid-bed technology requires optimization of several processing and formulation variables. The influence of a processing variable (nozzle orifice opening) and a few formulation variables (individual vs. combination plasticizer, or a water-insoluble additive) on dissolution of a model drug (acetaminophen) spray coated with Aquacoat® were studied. Pharmacodynamic and pharmacokinetic information for a model drug (acetaminophen) and computer simulation were used to develop a dosage form with a 12 hour sustained release for oral administration to children and adults for maximum analgesic and antipyretic effect. Simulated plasma acetaminophen concentration-time curves were similar to observed bioavailability study profiles. In vitro and preliminary in vivo results from an adult human volunteer indicate that sustained therapeutic saliva acetaminophen concentration is possible using the newly developed acetaminophen molded tablet dosage form. The bioavailability of the new, oral controlled release acetaminophen molded tablet relative to a commercially available product (Extra-Strength Tylenol® caplet) was evaluated in 8 healthy, adult volunteers. Multiple doses of these two products were administered in a two-way cross-over design. Bioavailability of the new sustained release molded tablet is comparable to that of the immediate release product. Polymer coated acetaminophen beads were effective in maintaining saliva acetaminophen concentrations of 5 μ/ml over a 12 hour dosing interval. / Graduation date: 1991

The hypotheses of this research were (1) to test if the antagonistic effect of ethanol on liver copper could be seen within a short period when ethanol ingestion, low dietary copper and high metabolic demand represented by either pregnancy plus lactation or rapid growth are simultaneously present and (2) to test if ethanol ingestion would exaggerate a marginal dietary copper status to an obvious copper deficiency. Pregnant rats were fed liquid diets containing either 0.75 (low) or 3.75 (control) mg copper/L with or without 30% of kcal from ethanol throughout gestation and the first 15 days of lactation. Maternal ethanol intake failed to exaggerate a marginal copper status to a copper deficient anemia in both dams and pups as estimated by concentrations of hemoglobin and liver iron and oxidase activity of the copper-metalloenzyme ceruloplasmin. However, maternal ethanol intake did depress maternal liver copper concentration when diet copper was low (interactive effect P<0.05). This effect was specific for liver because other tissue copper concentration was unaffected by ethanol. Although ethanol depressed total pup liver copper concentration regardless of dietary copper level, the interactive effect seen in maternal liver was reflected in copper content of the pup liver metallothionein fraction eluted from a Sephadex G-75 column. At least part of the depressive effect of ethanol on pup liver copper can be explained by elevated pup serum corticosterone (r=-0.61, P<0.001), a hormone known to enhance loss of neonatal liver copper by way of biliary excretion. On the other hand, the copper status of weanling female rats which were fed liquid diets containing either 0.5 (low) or 2.5 (control) mg copper/L for 5 weeks was unaffected by ethanol. Results demonstrate that the depressive effect of ethanol on liver copper can be seen within a period of weeks rather than months when ethanol ingestion, low dietary copper and pregnancy plus lactation are simultaneously present in contrast to non-pregnancy. This ethanol and copper interaction during reproduction, however, can not be detected if only either serum copper or oxidase activity of ceruloplasmin is used as an indicator of copper status. / Graduation date: 1989

Thesis (M.Phil.)--Hong Kong University of Science and Technology, 2009. / Includes bibliographical references (p. 106-121).

No description available.

Methylmercury (MeHg) is a potent neurotoxin capable of crossing the blood-brain barrier causing a profound negative impact on the central nervous system. After its release, Hg may be transported worldwide and eventually deposited in colder Arctic regions. Exposure of Aboriginal communities to MeHg occurs primarily through the consumption of traditional food. Dietary exposure studies are conducted using the total concentration of mercury in the food multiplied by the food consumption rate. This method does not take into account the oral bioavailability of Hg. Therefore, this study determines the bioavailability of Hg in four key traditional foods to provide a better estimation of Hg exposure and to improve the characterization of overall Hg risk to human health. We found that Hg concentrations significantly decreased for all foods after undergoing an in-vitro digestion process. Hg bioaccessibility percentage of ringed seal liver was 32.3%, ringed seal muscle was 69.0%, lake trout muscle was 28.8%, and lastly air-dried beluga muscle was 34.0%. Furthermore, no relationship was observed between bioaccessible Hg concentrations and original Hg concentrations in the raw food. The concentration of MeHg in the bioaccessible fraction was also examined and found to be significantly higher in muscle tissues than in the liver. Bioavailability of the foods was determined using Caco-2 cells. Hg bioavailability percentages were found to be 0.42% for RSL 5.24% for RSM, 7.30% for ADB, and finally, 12.70% for LT. Correlations were found between increased Hg uptake and higher percentages of bioaccessible MeHg as well as lower concentrations of bioaccessible selenium. Lastly, a significant decrease in MeHg uptake after 24 hours was observed when co-incubating with selenium. These results suggest that risk assessments should incorporate bioaccessibility and bioavailability when estimating mercury exposure. Additionally, nutrients such as selenium in traditional food may play a role in reducing mercury uptake in the gut.

No / Aims To determine the bioavailability of gentamicin to the lung following inhalation from two jet nebulizers. Methods Serial urine samples were obtained from 10 volunteers after a 80 mg dose given orally, nebulized from a Pari LC + (PARI) and MicroNeb III (MN) devices, or after a 40 mg intravenous dose. In vitro aerodynamic characteristics of the nebulized doses were also determined. Results The mean (SD) absolute gentamicin lung bioavailalibility following delivery by PARI and MN devices was 1.4 (0.4) and 1.7 (0.5) %. The mass median aerodynamic diameter (MMAD) of the drug particles from the PARI and MN systems was 8.6 (0.6) and 6.7 (0.5) µm and the corresponding fine particle doses (FPD) were 10.2 (2.8) and 11.7 (1.5) mg. Conclusions The MMAD and FPD data reflect the poor lung deposition of gentamicin identified by urinary excretion.