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Stereoselective pharmacokinetics and placental transfer of fluoxetine and norfluoxetine in pregnant sheep under steady-state conditions Chien, Caly


Fluoxetine (FX) is one of the most popular SSRIs used for the treatment of depression. Its use in treating depressed pregnant woman has increased substantially in recent years. A considerable amount of attention in the literature regarding the use of FX in pregnancy has been devoted to the assessment of birth outcomes following in utero FX exposures while studies that focus on pharmacokinetics during pregnancy are relatively sparse. Previous FX experiments in pregnant sheep using single dose intravenous (i.v.) bolus administration have focused primarily on the acute exposure and effects of the drug on both the mother and fetus. In the present studies, experiments were conducted to investigate the stereoselective pharmacokinetics of FX and norfluoxetine (NFX) under steady-state conditions in nonpregnant sheep and pregnant sheep at late gestation via continuous 8-day i.v. infusion of FX to the ewe. Drug infusions were conducted at two dose levels (i.e. low dose and high dose) in nonpregnant sheep that allowed the examination of nonlinear pharmacokinetics of FX in sheep. The pregnant sheep infusion experiment was to determine the impacts of pregnancy on the stereoselective pharmacokinetics of FX and NFX, and to assess the exposure of the fetus to FX and NFX enantiomers at steady-state. Moreover, a continuous 4- day direct fetal i.v. FX infusion experiment was conducted to study the pharmacokinetics of FX and NFX in fetal lambs in attempt to explore intrinsic drug elimination capability by the fetus. In nonpregnant sheep, FX and NFX enantiomers exhibited significant pharmacokinetic differences under steady-state conditions, confirming the observations made in previous i.v. bolus experiments. For FX, the R-enantiomer had a lower steady-state concentration (Css) level but a longer elimination half-life (t½β) than the S-enantiomer while for NFX, both the R- and S-enantiomers had similar Cs s levels but the t½β was slightly longer for R-NFX compared to S-NFX. FX and NFX also displayed stereospecific protein binding, with free fractions of the R-enantiomers that were about 2 to 3-fold higher than those of the Senantiomers. In comparison to humans, quantitative differences exist but qualitatively the overall stereoselective disposition of FX and NFX are similar between sheep and humans. Using the literature reported value for hepatic blood flow in sheep, the intrinsic clearances (CLint) for the FX enantiomers were determined. CLint of R-FX was estimated to be ~50% higher than that of S-FX, indicating that, in addition to stereoselective protein binding, stereoselective metabolism also played a pivotal role in the overall stereoselective disposition of FX. Moreover, FX displayed a disproportional change in pharmacokinetics in sheep upon long-term administration, characterized by a decrease in total body clearance (CLTB) and increase in dose normalized area under the curve (AUC) with higher dose. This nonlinearity may be due to inhibition of a CYP2D6-like enzyme in the sheep liver, as this is the major drug metabolizing enzyme for FX in humans. In pregnant sheep, the stereoselective pharmacokinetics of FX and NFX under steady-state conditions were similar to those observed in nonpregnant animals. No remarkable changes in the S/R ratio of FX and NFX were observed. Similarly, no change in FX clearance was observed as opposed to the previous finding of a higher clearance in pregnant sheep following single i.v. bolus administration. Protein binding did not appear to differ between pregnant and nonpregnant sheep for either FX and NFX. FX and NFX exhibited moderate degrees of placental transfer upon chronic administration, with a fetal-to-maternal (F/M) AUC ratios of about 0.40 and 0.33, respectively. When concentrations were corrected for the difference in free fraction between the maternal and fetal compartments, the F/M ratio still remained less than unity, suggesting the presence of other nonplacental routes of elimination for FX in the fetus. Analyses of amniotic and fetal tracheal fluids showed that excretion of FX and NFX into these fluids resulted in levels not exceeding those in fetal plasma and significant accumulations were therefore unlikely. Comparisons of F/M ratios between the R- and S-enantiomers revealed no difference between R-FX and S-FX, while S-NFX was slightly higher (-25%) compared to R-NFX, indicating that NFX distributed between the mother and the fetus in a stereoselective manner. Following fetal i.v. infusion of FX, alterations in fetal blood gas status, characterized by decreases in PO2 and O2 saturation, and increases in PCO2 and pH, were noted. Due to variability between animals, the majority of these effects did not reach statistical significance. The stereoselective pharmacokinetics of FX and NFX in fetal lambs were similar to those observed in adult sheep, but the extent of stereoselectivity in terms of the S/R ratio was less. The differential steady-state concentrations of the FX enantiomers observed in the fetal circulation were likely due to stereoselective protein binding in fetal plasma and differential maternal-to-fetal placental transfer of the enantiomers preceded by maternal stereoselective metabolism. Based on the F/M ratios for NFX (-0.62) following fetal FX infusion, it appears that the fetus has limited metabolic capability, if any, to biotransform FX to NFX. It is not fully known, however, whether other metabolic pathways such as the formation of trifluoromethylphenol via O-dealkylation are functional in the fetus. Renal excretion of FX and NFX did not contribute substantially to their overall clearance in the fetus (<1% of CLJB). In comparison to maternal and nonpregnant adult sheep, weight normalized CLTB, CLrenal, and Vdss were significantly higher in the fetus. Unbound fractions of FX and NFX were also higher in the fetus owning to the lower concentration of plasma protein in fetal plasma. The intrinsic capability of the fetus to eliminate FX was assessed by calculating the maternal and fetal placental and nonplacental clearances based on the 2-compartment model for the maternal-fetal unit. The results indicated that both placental and nonplacental routes were equally important in fetal elimination of FX. It is concluded that other elimination routes are likely present in the fetus but these remain to be elucidated.

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