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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.

The objective of this dissertation is to study the mechanism by which HIV protease inhibitors enter into the central nervous system (CNS) and breast milk of rats, and what effects MDR modulators have on the distribution and metabolism of HIV protease inhibitors. The transporter P-glycoprotein (P-gp) has been shown to limit the distribution of HIV protease inhibitors into the CNS of rodents. This thesis examined the effects of GF120918, an MDR modulator, on the CNS distribution of amprenavir, an HIV protease inhibitor, in rats. GF120918 significantly increased the unbound CNS concentrations of amprenavir without altering the unbound blood concentrations of amprenavir. The results of these studies show that GF120918 can inhibit P-gp at the blood brain barrier (BBB) to increase the unbound CNS concentration of amprenavir and potentially other HIV protease inhibitors. Many first generation MDR modulators inhibited both P-gp transport and CYP3A metabolism. Therefore, a principal goal of this thesis was to determine if GF120918 could selectively inhibit P-gp transport without inhibiting CYP3A metabolism. Using in vitro (human) and in vivo (rat) studies, GF120918 selectively inhibited P-gp at the BBB without inhibiting CYP3A metabolism. The transporter MRP1 has been shown to both transport HIV protease inhibitors and expressed in the CNS. Studies contained in the thesis have shown that mrp1 is not localized to the BBB of rats, therefore, mrp1 is unlikely to play a significant role in the distribution of HIV protease inhibitors into the CNS of rats. The distribution of nelfinavir, an HIV protease inhibitor, into rat breast milk was studied in the thesis as a first approach in understanding the extent to which HIV protease inhibitors can accumulate into milk. The concentration of nelfinavir in rat milk was approximately half that of plasma. P-gp protein expression was detected in lactating rat mammary tissue. However, GF120918 showed no effect on the distribution of nelfinavir into rat milk suggesting that P-gp does not play a significant role in the distribution of HIV protease inhibitors into milk.