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Pharmacokinetics and pharmacodynamics of the selective serotonin reuptake inhibitors, fluoxetine and paroxetine, during pregnancy and the nursing period Kim, John

Abstract

The prevalence of depressive disorders during pregnancy and the postpartum period and the need for continuous pharmacological intervention necessitate a better understanding of antidepressant disposition via placental transfer and breast-feeding. However, there is relatively limited information available for pharmacokinetics of these drugs. In the present studies, the pharmacokinetics of fluoxetine and paroxetine were examined and compared in humans and sheep. In order to characterize drug disposition, several sensitive analytical methods for quantitative determination of fluoxetine and norfluoxetine isomers and paroxetine were developed using GC/MS and LC/MS/MS. In humans and sheep, fluoxetine and norfluoxetine cross the placenta extensively. A relatively lower fetal-to-maternal ratio of paroxetine compared to fluoxetine was observed in humans. In adults, fluoxetine is extensively metabolized; however, minimal metabolic capacity was observed in human and ovine fetus. In the fetal lamb, no detectable concentrations of norfluoxetine isomers were observed in fetal plasma and amniotic fluid following fetal fluoxetine administration. Limited accumulation of fluoxetine in amniotic fluids was observed in fetal lamb unlike other basic amine drugs. In humans, serum neonatal fluoxetine and norfluoxetine concentrations were remained elevated following birth and slowly declined. These data were consistent with an in vitro metabolism study in sheep, which indicated lack of fetal N-demethylation in contrast to adult microsomes. In contrast, neonatal paroxetine concentration declined rapidly following birth. In fetal lambs, moderate transient changes in blood gas status were observed following fluoxetine administration. However, in both fluoxetine- and paroxetine-exposed human gravida, neither significant changes in birth-outcome nor perinatal complications were observed. Fluoxetine, norfluoxetine and paroxetine are excreted in human breast milk with the milk-toserum ratio higher for fluoxetine compared to paroxetine, which resulted in relatively higher exposure to fluoxetine in combination with relatively lower metabolic capacity in the neonate. Serum drug concentrations were also measured in nursing infants, and detectable levels of fluoxetine and norfluoxetine were observed in infants younger than 2 months. Compared to adult ewes, significant changes in total body clearance, half-life and steadystate volume of distribution were observed in pregnant ewes. In addition, the stereoselective disposition of fluoxetine isomers was observed in both humans and sheep. In sheep, stereoselective pharmacokinetics following a single dose are mainly mediated by stereoselective plasma protein binding. However, during chronic therapy, stereoselective drug metabolism along with fluoxetine-mediated inhibition of hepatic enzymes is responsible for stereoselectivity. Clearance- and exposure time-dependency of stereoselective disposition was observed in both species. Therefore, stereoselectivity during chronic dosing may be mediated by the inhibition of CYP2D6 by fluoxetine and norfluoxetine and stereoselective metabolism of fluoxetine by CYP2C9/19. In conclusion, the present studies present the first detailed pharmacokinetics of fluoxetine and paroxetine during pregnancy and the nursing period, which suggest relatively lower exposure of paroxetine compared to fluoxetine. Furthermore, stereoselective disposition of fluoxetine was examined during both acute and chronic administration, and potential mechanisms were proposed.

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