Thèse (Ph. D.)--Université Laval, 2003. / Bibliogr.: f. 152-193. Publié aussi en version électronique.

Thèse (M.Sc.)--Université Laval, 2000. / Bibliogr.: f. 127-134.A. Publié aussi en version électronique.

Thesis (Ph. D.)--University of Washington, 2005. / Vita. Includes bibliographical references (leaves 64-83).

Thesis (Ph.D.) - University of Queensland, 2006. / Includes bibliographical references.

Thesis (Ph. D.)--University of Rhode Island, 2005. / Typescript. Includes bibliographical references (leaves 129-140).

Thesis (Ph. D.)--University of Washington, 2006. / Includes bibliographical references (leaves 180-197).

Thesis (Ph. D.)--West Virginia University, 2001. / Title from document title page. Document formatted into pages; contains xiv, 150 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 104-120).

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

The oral route of administration is the most widely used mode of drug administration due to advantages such as the convenience of oral drug administration, patient choice, cost-effectiveness, and ease of generating oral dosage forms on a large scale. How effectively an oral drug is absorbed and made accessible to the target organ depends on a variety of factors. Poor absorption from the absorption site, excessive metabolism in the gut and liver, and pharmacokinetic drug-drug (PK-DDI) interactions can all contribute to inadequate therapy. The PK-DDI may result in greater than anticipated bioavailability and toxicity due to irreversible enzyme inhibition including time-dependent inactivation (TDI) of the intestinal enzymes.There are different in vitro models available to predict the fraction escaping gut metabolism (Fg), which is a major determinant of intestinal bioavailability. On the other hand, using pre-clinical species, Fg can be extrapolated in humans using allometric scaling, but there has been significant discordance due to the variable intestinal metabolism in humans vs. pre-clinical species. A number of absorption models have been developed over the years to predict oral drug absorption, and intestinal TDI can be incorporated into many of those models. In this study, the continuous intestinal absorption model has been refined, including the intestinal metabolism model, to predict the oral absorption of midazolam and nicardipine in both humans and rats. This absorption model was also used to predict the Fg of these drugs in those two species. The in vitro metabolic characteristics of the model drugs were investigated using both human and rat microsomes. The kinetic profiles of their metabolic conversion in rats and humans were developed using numerical techniques. The continuous absorption model explains how drug concentration changes with time and distance. A physiologically based pharmacokinetic (PBPK) model describes the intestine. The physiological inputs to the model, as well as the structure of the gastrointestinal tract, vary depending on the species. Rats and humans have different lengths of the small intestine's regions, such as the jejunum, and absorptive surface area amplifiers, such as the villi and microvilli. Along with the metabolic characteristics established through in vitro metabolic investigations, physiological aspects (applied to both rats and humans) and physicochemical drug characteristics were also added to the model. To estimate the absorption characteristics of midazolam and nicardipine, this model was further connected to the traditional compartmental model that represents the rest of the body. Chapter one details the background and importance concerning this project, along with the hypothesis and goals. Chapter two involves developing and validating bioanalytical methods for the drugs of interest. Chapters three and four detail the in vitro metabolic studies in rat and human microsomes (both intestinal and liver). Chapter five represents the TDI studies which were finally excluded from the absorption modeling in this thesis. Finally, chapter six illustrates the prediction of the oral PK profile of midazolam and nicardipine in rats and humans, rendering predicted values of Fg of these drugs in both species. Finally, chapter seven presents the significance, summary, and some directions to take this research further down the future. / Pharmaceutical Sciences

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