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.

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.