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UBC Theses and Dissertations

The disposition of fluoxetine in newborn lambs up to one year of age Chow, Timothy W. Y.


While drugs are commonly used in the pediatric population, their disposition is not well studied. The passive transfer of drugs administered to pregnant women to the fetus constitutes a major route of drug exposure in newborns. The fetus has maternal routes for drug disposition; however, newborns must rely on their own immature mechanisms. Therefore, a thorough understanding of the ability of newborns to absorb, distribute, metabolize. and excrete drugs, and the ontogeny of drug disposition is essential to determine the development of these mechanisms from birth to adult life with the goal of providing clinicians with guidelines for optimal drug dosing. The lifetime incidence of depression in women is approximately 10-25% with a greater vulnerability for the onset or recurrence of depression during childbearing years. Approximately 30-35% of pregnant women diagnosed with depression are on an antidepressant, such as the selective serotonin reuptake inhibitors (SSRI). One of the most prescribed SSRIs that is also used during pregnancy is fluoxetine. The prevalence of SSRI use during pregnancy results in 5% of all newborns in our population with antenatal SSRI exposure. Stereoselective disposition of fluoxetine has been demonstrated in sheep and humans. This thesis utilized the chronically catheterized lamb animal model to study fluoxetine disposition ability from newborn to one year of life. This model builds upon previous research in our group that used pregnant, non-pregnant, and newborn sheep to characterize the maternal, fetal, and neonatal disposition of clinically relevant compounds. The studies in this thesis on postnatal fluoxetine disposition build upon previous research on maternal-fetal fluoxetine stereoselective disposition in our group. These studies reported no metabolism of fluoxetine in the fetus, and their disposition depended on maternal routes. The disposition of fluoxetine in newborn lambs was limited compared to adults but was developed compared to the fetus. A gender difference was observed in the newborn group where females had a greater metabolic capacity for fluoxetine. A significant maturation in drug disposition was observed at approximately 3 months, which coincided with the time of weaning. Fluoxetine disposition was stereoselective from newborn to one year of age.

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