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.

Although concentrated solar power can be used to produce power using traditional electricity generation, energy storage has become a problem due to the intermittent supply of solar energy. By using solar energy in chemical production processes, the solar energy can be stored in a useful chemical product. The purpose of this thesis will be to examine the possibilities of a new solar chemical cycle the produces iron and ethylene from hematite (a form of iron oxide) and ethane using concentrated solar power. These two products are important stepping stones in the production of steel and polymers. This process could allow for the current process of steel production to move away from processes using coal and towards a more sustainable process using the hydrogen formed from the ethane cracking process and solar energy. The thesis will include: (1) the development of a new solar powered iron and ethylene combined cycle, (2) a feasibility study of a Concentrated Solar Heat Supply System (CSHSS) being developed at Georgia Tech, and (3) an assessment of the proposed cycle. The assessment will include an estimate of production including a thermodynamic ASPEN model, assessment of research to realize actualization of the theoretical cycle, an exergy analysis, and a heat exchanger analysis for the exchange of heat between the CSHSS and the chemical process.