Year: 2016
Type: dissertation
Abstract: Inflammation-mediated changes in drug disposition commonly involve alterations in the expression of drug transporters and drug metabolizing enzymes. Placental drug transporters including ABC and SLC drug transporters are major determinants of fetal drug exposure. We hypothesized that inflammatory conditions during pregnancy would impact fetal drug exposure through alterations in placental transporter expression. Two inflammatory conditions were examined as part of this thesis, HIV infection and obesity. In a series of in vivo studies, pregnant HIV-Transgenic rats (HIV-Tg) as well as pregnant wild-type rats were administered bacterial endotoxin to model the presence of endotoxemia in HIV patients. Endotoxin administration significantly downregulated numerous placental and hepatic drug transporters in both HIV-Tg and WT rats. In addition, the presence of the HIV transgene along with bacterial endotoxin further downregulated the expression of placental P-gp, OATP2B1 and Slco4a1 than was detected with either inflammatory condition alone. This was attributed to an augmented inflammatory response to endotoxin in HIV-Tg rats. Overall the findings of these studies will aid in better predicting drug-disease interactions. As many ART are highly influenced by transporter mediated processes, this will assist in optimizing maternal treatment as well as minimizing vertical transmission and/or fetal toxicity. A second inflammatory condition investigated in this thesis is maternal obesity; which is a low-grade chronic inflammatory condition. However, in an in vivo model of maternal obesity, obesity was neither associated with a measurable inflammatory response, nor was it associated with significant changes in drug transporter expression.
Source: TSpace (University of Toronto)
Author: Ragia H. Ghoneim
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3159019305