This dissertation research involved investigations into possible drug-nutrient or disease-nutrient transport interactions in the nursing mother-neonate dyad. The overall hypothesis was that cefepime would inhibit L-carnitine transport at the lactating mammary gland and in developing neonates. Additionally, inflammation would alter energy substrate transporter expression in mammary tissue.<p>
The first objective was to investigate the potential for drug-nutrient transport interactions at the lactating mammary gland. A continuous cefepime infusion to lactating rats reduced L-carnitine transfer into milk at early but not mid lactation. In conjunction with higher milk L-carnitine and cefepime concentrations and higher expression levels of Octn2, the data suggests cefepime competitively inhibited Octn2-mediated L-carnitine transport into milk.<p>
The second objective was to assess the influence of lactation stage on milk-to-serum ratios (M/S) for an actively transported drug, cefepime, and its impact on the calculation of neonatal exposure indices. Higher cefepime M/S on day 4 lactation versus day 10 coupled with lower systemic clearance values for cefepime in postnatal day 4 versus day 10 pups resulted in >7-fold higher exposure index values at postnatal day 4. These data confirm the need to determine M/S at different lactation stages for actively transported drugs to avoid over- or underestimation of neonatal exposure risk.<p>
The third objective was to examine a drug-nutrient transporter interaction in neonates. Cefepime administered twice daily according to different dosing schedules (postnatal days 1-4, 1-8, 8-11, 8-20 and 1-20) caused significant alterations in the ontogenesis of several mechanisms involved in the L-carnitine homeostasis. These alterations likely represented adaptive responses to cefepime inhibition of L-carnitine transport. Furthermore, these changes seemed to depend on duration and timing of exposure relative to postnatal maturation.<p>
The fourth objective was to examine the effects of inflammatory stimuli on energy substrate transporter expression in mammary tissue. Inflammatory stimuli altered expression of glucose, fatty acid and L-carnitine transporters in mammary tissue <i>in vitro</i> and <i>in vivo</i>.<p>
Collectively, this research provided experimental evidence for significant disease- or drug-nutrient transport interactions in the nursing mother-neonate dyad. Further research may identify a need for dietary modification during pharmacological management of disease in the nursing mother-neonate dyad.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:SSU.etd-02042010-092016 |
| Date | 05 February 2010 |
| Creators | Ling, Binbing |
| Contributors | Maenz, David D., Paterson, Phyllis G., Zello, Gordon A., Alcorn, Jane, Krol, Ed S., Olkowski, Andrew A. |
| Publisher | University of Saskatchewan |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://library.usask.ca/theses/available/etd-02042010-092016/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Saskatchewan or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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