Digitized by Kansas Correctional Industries

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Spectrophotometric studies have been carried out to determine the pH dependence of binding of SKF 525 A, Brietal sodium and carbon monoxide to cytochrome P-450. The optimal pH for metabolic conversion of SKF 525 A has been investigated and this agent and its major metabolite, SKF 8742 A, have been metabolised in vitro by swine and rat hepatic microsomes. A suitable gas liquid chromatography assay has been developed and used to analyse metabolic production. The effects of carbon monoxide, dithiothreitol, n-octylamine and of induction of cytochrome P-450 by phenobarbital on metabolism of SKF 525 A and SKF 8742 A have been investigated. Attempts have been made to synthesise SKF 525 AN-oxide. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

This dissertation describes formulation of a gastric retention device (GRD) and sustained release (SR) hydrochlorothiazide beads at Oregon State University. Formulation condition and amounts of excipients had significant influence on characteristic of the GRD. The GRD containing SR hydrochlorothiazide beads was employed to assess bioavailability/bioequivalency study in healthy subjects. An original GRD was retained in the stomach with food and completed the drug release. However, this original GRD failed to stay on an empty stomach, leading to lower bioavailability than an immediate release (IR) tablet due to insufficient rigidity. The original device was modified to be more rigid, and this more rigid device successfully stayed on an empty stomach and achieved completion of the drug release at a slow release rate, the bioavailability and the drug effect on diuresis increased compared to the drug in an IR tablet. Less amount of hydrochlorothiazide at a slow release rate achieved equivalent diuresis to higher amount of the drug at a rapid release rate, which indicated slow drug release resulted in higher efficiency of hydrochlorothiazide. In vivo/in vitro correlation of hydrochlorothiazide in a modified GRD and an IR tablet was established to predict in vivo profile with in vitro dissolution profile prior to a clinical study. Pharmacokinetic/pharmacodynamic of nicotine was reviewed in terms of a relationship between plasma nicotine concentrations and pharmacological changes including heart rate and craving. Considering craving and development of tolerance to nicotine effect on cardio-acceleration, a dosing regimen with a combination of rapid input and constant slow input was suggested to improve smoking cessation. A simulation study was carried out to verify the current regulatory policy on assessing bioequivalency of enantiomeric drugs. First-order dissolution and absorption process, and nonlinear stereo-specific pre-systemic and systemic metabolism was taken into account to establish a pharmacokinetic model for the simulation. Four different dissolution profiles, within- and between-subject variability, dose and sample size were considered to simulate 1000 cross-over bioequivalency trials under standard bioequivalency criteria. Probability of false positives was determined to evaluate the current policy. The simulation study validated the importance of individual enantiomer pharmacokinetic for assessing bioequivalency study of the chiral drugs. / Graduation date: 2003

published_or_final_version / Biochemistry / Master / Master of Philosophy

A novel approach using smoothing cubic splines and point-area deconvolution to estimate the absorption kinetics of linear systems has been investigated. A smoothing cubic spline is employed as an interpolation function since it is superior to polynomials and other functions commonly used for representation of empirical data in several aspects. An advantage of the method is that results obtained from the same data set will be more consistent, irrespective of who runs the program or how many times you run it. In addition, no initial estimates are needed to run the program. The same sampling time or equally spaced measurement of unit impulse response and response of interest is not required. The method is compared with another method by using simulated data containing various degrees of random noise.

The stereo-chemistry, structure activity relationships and the metabolism of the anorectic drug, diethylpropion hydrochloride, have been reviewed briefly, together with the analytical methods for the determination of this drug and its metabolites in biological fluids. In addition, the physico-chemical properties, mode of action, pharmacology and uses of the metabolites have been presented. A comprehensive review on general principles of salivary excretion of drugs and their therapeutic drug monitoring in saliva with relevant published data on saliva/plasma drug concentration relationships has been outlined. Sensitive and specific assay procedures, based on gas-liquid chromatography for the identification, separation and determination of diethylpropion and its two major metabolites i.e. ethylaminopropiophenone (11) and diethylnorpseudoephedrine (IV) in aqueous and biological fluids, have been developed. These methods were used to study the urinary excreUon as well as saliva and plasma levels of the two major metabolites and, where possible, the unchanged drug, in man. Sustained release pellets with diffusion rate-controlled membranes were employed to control the rate of input into the body by oral or rectal route of administration. Urinary excretion data and plasma levels of metabolites 11 and IV in volunteers, where the urine was controlled at an acidic pH, were used for the evaluation of the bioavailabilities of different dosage forms of diethylpropion hydrochloride. The concentrations of metabolites 11 and IV were also measured in saliva and in plasma after administration of the drug in different doses and dosage forms: relationships between saliva and plasma concentrations (S/P) and between urinary excretion rates and plasma concentrations (U/P) were developed for each of the two metabolites during plateau levels after oral administration of the sustained release pellets (Lot R 7773). The potential use of salivary excretion of the metabolites as an index to monitor their plasma levels and bioavailabilities, was examined. The distinct advantage of using a subdivided controlled release system (i. .e. sustained release pellets) to a single unit sustained release tablet (erosion-core type) in relation to influence of the physical presence of food on the rate and extent of absorption has been demons t rated . It was found that the route of administration (oral or rectal) did not significantly affect the bioavailability of the sustained release pellets. The study also involved the investigation of the release of the drug from the pellets. Because the release control step was diffusion, no significant influences on dissolution rates were observed with the use of different dissolution test models and agitation intensities. The influence of the concentration and composition (presence of cations viz. Na+ and K+ i~r anions viz . phosphate and borate) of the dissolution medium on the release of the drug from sustained release pellets, was also studied. Any potential changes in the dissolution pattern on storage of the pellets under different conditions (4°C, room temperature and 37°C) ovrr, a period of at least one year, were investigated. The in vitro and in vivo correlations of two lots of sustained release pellets, each exhibiting different dissolution profiles, and administered rectally and orally, were developed: the in vitro data on the free drug were related to the sum of the urinary excretion data of metabolites II and IV. An attempt to use an empirical approach to predict urinary excretion rate profiles of metabolite II after oral administration of the sustained release pellets, was promising; the calculated profiles were reasonably comparable with those of in vivo studies. However, the complete validity of such equations needs further investigations. / Thesis (Ph.D.)-University of Durban-Westville, 1984.

The ability to metabolise drugs and achieve positive therapeutic outcomes is dependent on both genetic and environmental factors. The focus of this study was to determine the distribution and frequency of clinically relevant DME alleles and to assess the impact of these DME alleles on therapeutic outcomes in a cohort of 50 HIV-TB co-infected Zulu participants. PCR-RFLP was used to generate a genotypic profile of CYPIA2, 2C9, 2C19, 2E1, 3A4, MDR-1 and NAT-2. The distributions of the allelic frequencies were as follows. The CYPIA2 (A) - 50.7%, CYP2C9*2 — 100% and *3 — 56.2%, CYP2C19*2 — 35.4%, CYP2E1 (C2) — 28.4%, CYP3A4*1B (G) — 58.2%, MDR-1 (C3435T) - 16% and NAT-2 slow acetylators — 6.5%. Seventy-three percent of participants had prolonged TB therapy. Within this group, 82.9% of patient displayed wild type and 17.2% variant allele for CYP2E1 gene (p= 0.04) profile. In addition, all the slow acetylators in this study had prolonged TB therapy. In the MDR-1 gene, 87.5% showed wild type allele and 12.5% displayed the variant allele. Unsuccessful TB outcomes were also noted in 22% of this study population. In this group the variant allele was found to be dominant in CYPIA2, CYP3A4 and NAT-2, the opposite was seen in CYP2E1 and MDR-1. It was also interesting to note a similar genetic profile in the group that showed successful TB therapy outcomes. All participants had positive ARV treatment outcomes despite DME genotypic variations. However, 26% of all study participants experienced liver enzyme abnormalities. These findings concur with other studies regarding the ethnic distribution of DME alleles and evidence of an association between ART and TB therapeutic outcomes and DME genotype variation was inconclusive. / Thesis (M.Med.Sc.)-University of KwaZulu-Natal, Durban, 2007.

Cytochrome P-450, the terminal oxidase of the metabolic mono-oxygenase system, is thought to exist in multiple forms, which have differing substrate specificities, and are variably inducible by different enzyme inducers. Many mutagens, themselves unreactive, require metabolic activation by one or more of these cytochrome P-450-dependent microsomal enzymes for mutagenic activity. Such mutagens may be detected in the Salmonella mutagenicity test only by the incorporation of an hepatic microsomal (59) fraction into the assay (as a first approximation to in vivo metabolism). Induction of the microsomal enzymes by different agents enhances the metabolic activation of mutagens; in fact, many mutagens are only detected when the 59 fraction has been induced by appropriate agents. Inducers of the phenobarbital-type are known to enhance microsomal steroid hydroxylation when administered at supraphysiological levels, inducers of several mono-oxygenase activities. In turn, the steroids, have been reported to be The inductive effects of the female sex-steroids and the combined effects of steroid and phenobarbital (PB) pretreatment on the metabolic activation of four mutagens have been investigated using the Salmonella assay. Female Sprague-Dawley rats were pret reated with 17a-oestradiol (E2) or progesterone (PRG) , at a level of either 1 mg/kg or 20 mg / kg daily for 14 days. A duplicate set of similarly pretreated groups were also induced with PB. Hepatic microsomal fractions were prepared from each group and incubated with each of the te st mutagens in the presence of a tester strain known to detect each particular type of mutagen. Induction of the hepatic metabolizing system by PB increased the activation of the mutagens significantly (as reflected by an increased number of revertant prototrophic S .typhimurium colonies). The administration of PRG also caused significant, and dose-dependent, induction of the activation of af l atoxin B1, benzo(a)pyrene, and dimethylnitrosamine. In general, E2 exhibited no inductive effect, but it did produce an increase in the activation of aflatoxin B1 (a reaction which is known to be catalysed by a mono-oxygenase prefe rentially inducible by PB). When use was made of a microsomal fraction that was prepared from animals which were both steroidpretreated and induced by PB, mutagenic activation was of the same order of magnitude as that observed when induction was brought about by PB alone. The absence of additive effect, taken together with the observations already mentioned, indicate that steroids induce the same cytochrome isozymes that are induced by PB. The implications of sex-hormonal regulation of the metabolic activation of mutagens are briefly discussed. / KMBT_363 / Adobe Acrobat 9.53 Paper Capture Plug-in