Placental transfer and fetal distribution of fluoxetine in the rat.
Previously conducted reproduction and teratology studies in rats (unpublished observations) exposed to fluoxetine have revealed no compound-related adverse effects on fertility and no teratogenic effects. In order to confirm embryonic/fetal exposure to fluoxetine and/or metabolites, dissection and whole-body autoradiographic techniques were utilized to determine the placental transfer and fetal distribution in 12- and 18-day-pregnant Wistar rats 1, 4, 8, and 24 hr following a single oral 12.5 mg/kg dose of [14C]fluoxetine. On gestation Days 12 (organogenesis) and 18 (postorganogenesis), peak concentrations of radiocarbon occurred 4-8 hr after dose administration in the placenta, embryo/fetus, amniotic fluid, and maternal kidney, brain, and lung, and declined slightly at 24 hr postdose. Maternal lung contained the highest tissue concentration of radiocarbon at all time points. Placenta and maternal brain, kidney, and liver contained moderate levels of radioactivity, while embryonic/fetal tissue, amniotic fluid, and maternal plasma contained low levels of radioactivity. Mean fetal concentrations of radiocarbon at 4, 8, and 24 hr on gestation Day 18 were higher than mean embryonic concentrations on Day 12 of gestation. Analytical characterization of radioactivity indicated that combined fluoxetine and norfluoxetine concentrations accounted for 63-80% of the total radiocarbon concentrations in embryonic/fetal tissue. Results indicated that embryonic/fetal and maternal tissue levels of fluoxetine were greatest at early time points and declined with time, while norfluoxetine tissue levels were highest at the 24-hr time point. Whole-body autoradiographic techniques demonstrated that radioactivity associated with [14C]fluoxetine and/or its metabolites traversed the placenta and distributed throughout the 18-day fetus 4 hr following dose administration. Visual and quantitative evaluations of the autoradiograms indicated that the highest fetal concentrations of radiocarbon were associated with brain and thymus. Results from these studies indicate that fluoxetine and norfluoxetine traverse the placenta and distribute within the embryo/fetus during the periods of organogenesis and postorganogenesis and confirm embryonic/fetal exposure of parent and metabolite in previous negative rat teratology and reproductive studies.
Pohland
R C
RC
Toxicology Division, Eli Lilly and Company, Greenfield, Indiana 46140.
Byrd
T K
TK
Hamilton
M
M
Koons
J R
JR
D000818:Animals; D001345:Autoradiography; D005260:Female; D005333:Fetus / Q000378:metabolism*; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D008431:Maternal-Fetal Exchange; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D005473:Fluoxetine; C036139:norfluoxetine