Drug/inflammation nutrient transport interaction in the lactating 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. 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. 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. 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. 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 in vitro and in vivo. 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