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.
Footnotes
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↵3 Abbreviations used are: SSRI, serotonin reuptake inhibitor; FX, fluoxetine; NFX, norfluoxetine; SFX, (S)-fluoxetine; SNFX, (S)-norfluoxetine; RNFX, (R)-norfluoxetine; CL, total body or systemic clearance; AUC, area under the plasma concentration versus time curve; MRT, mean residence time;Vdss, volume of distribution at steady-state; AUC, area under the drug concentration versus time curve; t1/2β, apparent terminal elimination half-life; CLmp, maternal placental clearance; CLf, total fetal clearance; CLfp, fetal placental clearance; CLm, total maternal clearance; CLmn, maternal nonplacental clearance; CLfn, fetal nonplacental clearance; RFX, (R)-fluoxetine; F/M, fetal-maternal; P450, cytochrome P450; Σ amount, cumulative amount excreted; CLR, renal clearance.
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Funding from the Canadian Institutes of Health Research supported this study. D.W.R. is the recipient of an Investigatorship Award from the BC Research Institute for Children's & Women's Health.
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↵1 Present address: LG Chem Investment Limited, Seoul, Republic of Korea.
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↵2 Present address: Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia., Vancouver, BC, Canada.
- Received March 17, 2003.
- Accepted October 1, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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