Stereoselective Pharmacokinetics of Fluoxetine and Norfluoxetine Enantiomers in Pregnant Sheep

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:We examined the stereoselective disposition of fluoxetine (FX) and its metabolite norfluoxetine (NFX) in five pregnant sheep. Racemic FX was administered i.v. to the ewe (50 mg) and the fetus (10 mg) on separate occasions. Maternal and fetal blood, maternal urine, and fetal amniotic and tracheal fluid samples were collected for 72 h. FX and NFX isomers were quantified by gas chromatographymass spectrometry. They rapidly crossed the placenta [maternal to fetal area under the plasma concentration versus time curve (AUC) ratios 0.59 and 0.65, respectively]. There was significant FX stereoselectivity with S/R FX AUC ratios averaging 1.65 ؎ 0.33 and 1.73 ؎ 0.29 in ewe and fetus, respectively, after maternal dosing. The maternal clearance and volume of distribution were also higher for (R)-fluoxetine than for (S)-fluoxetine. FX, NFX, and their glucuronides were present in maternal urine but accounted for only 3.4% of maternal drug elimination. In contrast, NFX was not detected in the fetus after fetal FX administration, which is consistent with the absence of measurable fetal nonplacental clearance of the drug and the lack of NFX formation in fetal hepatic microsomal incubations. There was also no fetal production of FX and NFX glucuronides in vivo. Both FX and NFX were extensively and stereoselectively bound in maternal and fetal plasma, with the free fraction S/R FX ratio averaging 0.46 ؎ 0.06 and 0.58 ؎ 0.10 in ewe and fetus, respectively. Thus, FX exhibits extensive stereoselective disposition, which is likely due to differential plasma protein binding of the FX isomers, and there is no detectable fetal formation of NFX, FX, and NFX glucuronides.

Chronic Maternal Fluoxetine Infusion in Pregnant Sheep: Effects on the Maternal and Fetal Hypothalamic-Pituitary-Adrenal Axes

“…At 0700 h on infusion d 1, a 10-mL bolus injection of either 70 mg FX or sterile water was given over 2 min into the maternal femoral vein catheter followed by continuous infusion of 98.5 g/kg/d FX or an equivalent volume of sterile water for 8 d. The loading dose and infusion rate were calculated based on volume of distribution and systemic clearance data obtained from FX i.v. bolus pharmacokinetic studies in pregnant sheep previously performed in our laboratory (25). At 0700 h each day, maternal and fetal blood samples were collected for analysis of blood gases (1 mL) and plasma concentration of FX, cortisol, and ACTH (1.5 mL) and stored at Ϫ20°C for 2 wk and then at Ϫ80°C.…”

“…A rapid, sensitive, and selective chiral assay for FX and NFX enantiomers using gas chromatography mass spectrometry with selective ion monitoring developed in our laboratory was used for plasma FX analysis as previously described (25). Samples were analyzed for plasma FX and NFX concentrations only if maternal and fetal blood samples were collected at all time points in the protocols from 0700 h on the preinfusion day to 72 h postinfusion (n ϭ 6).…”

“…Placental transfer of FX has been demonstrated in the rat (23), human (24), and sheep (25). In adults, FX is metabolized to norfluoxetine (NFX), which also has antidepressant activity; however, in pregnant sheep, NFX has not been detected in the fetus after fetal drug administration, suggesting that FX is not metabolized in the fetus (24,26).…”

Fluoxetine Metabolism and Pharmacological Interactions: The Role of Cytochrome P450

“…The same experiments showed that radioactivity (i.e., FLU and/or its metabolites) crosses the placenta about 4 hours after drug administration, and accumulates in the brain and the thymus [81]. In pregnant sheep, FLU rapidly crosses the placenta after maternal administration; the foetus shows no demethylation nor glucuronidation activity and in both ewe and foetus FLU is extensively bound to plasma proteins [82]. Studies on isolated perfused human placenta (obtained immediately after delivery) have been carried out.…”

Milk Excretion and Placental Transfer Studies

“…A thorough nonclinical study to evaluate the placental transfer of fl uoxetine in sheep was performed by Kim et al (2004) . Using catheterized sheep, it was possible to administer fl uoxetine to either the ewe or the fetus and collect multiple maternal and fetal blood samples.…”