Pharmacokinetics and Transplacental Transfer of Fluoxetine Enantiomers and Their Metabolites in Pregnant Women

Abstract

Considering that fluoxetine (FLX) is used to treat depressive states during pregnancy and that it is a cytochrome P450 (CYP)2D6 inhibitor, which is involved in the metabolism of both of its enantiomers, this study aims to describe the enantioselective distribution and metabolism of FLX and of its metabolite norfluoxetine (NorFLX) following a single oral dose. Nine healthy pregnant women received 20 mg FLX at 32 weeks of gestation and later at the day of delivery. The apparent clearance of (S)-(+)-FLX (1.45 vs. 0.66 L/hour/kg) and the area under the plasma concentration vs. time curve (AUC) of the (S)-(+)-NorFLX (AUC 0-∞ 942.7 vs. 498.6 ng hour/mL) were higher (P < 0.05) than those of the respective (R)-(−) enantiomers, indicating that the (S)-(+)-FLX enantiomer is preferentially metabolized to (S)-(+)-NorFLX. The placental transfer (umbilical vein/maternal vein) of FLX and NorFLX is low (30-40%), with the predominant transfer of (S)-(+)-FLX (44 vs. 33%). The distribution of the enantiomers of FLX and NorFLX to amniotic fluid is low (< 10%).

Antidepressants and Antipsychotics in Human Pregnancy: Transfer Across the Placenta and Opportunities for Modeling Studies

“…Interestingly, for fluoxetine and norfluoxetine, transplacental transfer appeared to be enantioselective with the (R)-isomer showing on average a significantly lower F:M ratio than its (S)-isomer. 65,66,68 Hendrick et al reported the time after last fluoxetine dose for each F:M concentration ratio; however, no linear correlation between them could be found (P = .768). 61 The same holds true for the dose that varied between 10 mg and 60 mg per day, where no linear correlation between the F:M concentration ratio and dose was supported (P = .186).…”

“…There is ample evidence that fluoxetine and norfluoxetine (desmethylfluoxetine) cross the human placenta readily. 50,54,55,61,[65][66][67][68] Pooling all data on fluoxetine results in an overall mean ± SD F:M concentration ratio of 0.73 ± 0.29 (n = 54), with the values reported on an individual basis ranging from 0.23 to 1.55 (n = 34). For norfluoxetine, the overall mean ± SD is 0.79 ± 0.29 (n = 54), whereas the values reported on an individual basis ranged from 0.12 to 1.58 (n = 34).…”

“…There is ample evidence that fluoxetine and norfluoxetine (desmethylfluoxetine) cross the human placenta readily 50,54,55,61,65‐68 . Pooling all data on fluoxetine results in an overall mean ± SD F:M concentration ratio of 0.73 ± 0.29 (n = 54), with the values reported on an individual basis ranging from 0.23 to 1.55 (n = 34).…”

Study of some parameters of pregnant women with diabetes as well as anemia

“…The device displays the blood glucose level within several seconds. (17) After completing the examination, place a weak piece of cotton on the point to stop blood bleeding and absorb (clean) the rest of it.…”

Evaluación de la maduración y calidad espermática epididimaria en ratas macho adultas expuestas a fluoxetina durante la gestación y lactancia

“…Los estudios hechos en mujeres embarazadas y lactantes han observado que las concentraciones de FLX y norfluoxetina al momento del nacimiento en el suero del cordón umbilical en el feto son más bajas comparadas con respecto a las madres oscilando entre 0.61 y 0.68 ng/ml para FLX y entre 0.65 y 0.71ng/ml para norfluoxetina respectivamente (Hendrick et al, 2003;Kim et al, 2006;Rampono et al, 2004). La transferencia placentaria llevada a cabo a través de la vena umbilical/vena materna de la FLX y su metabolito oscila entre el 30% y 40%, además, su presencia en el líquido amniótico se ha demostrado es menor al 10% (Carvalho et al, 2018). En la leche materna la presencia de este fármaco es relativamente pequeña, y se ha observado que se excreta entre el 3 y 6 % de FLX intacta (Hendrick et al, 2001;Kim et al, 2006).…”