Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmac
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RESEARCH PAPER
Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics Leonardo Pinto 1 & Fernanda de Lima Moreira 1 & Glauco Henrique Balthazar Nardotto 1 Ricardo Carvalho Cavalli 2 & Elaine Christine Dantas Moisés 2 & Geraldo Duarte 2 Vera Lucia Lanchote 1
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Received: 8 May 2020 / Accepted: 9 June 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
ABSTRACT Background and Objective Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for Pglycoprotein (P-gp). Fexofenadine, an in vivo P-gp probe, is an antihistamine drug for seasonal allergic rhinitis and chronic urticaria treatment during pregnancy and it is available as a racemic mixture. This study evaluated the chiral discrimination of P-gp investigating the effect of fluoxetine on maternalfetal pharmacokinetics of fexofenadine. Methods Healthy parturient women received either a single oral dose of 60 mg racemic fexofenadine (Control group; n = 8) or a single oral dose of 40 mg racemic fluoxetine 3 h before a single oral dose of 60 mg racemic fexofenadine (Interaction group; n = 8). Maternal blood and urine samples were collected up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected.
Results The maternal pharmacokinetics of fexofenadine was enantioselective (AUC0–∞R-(+)/S-(−) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC0-∞ (267.7 vs 376.1 ng.h/mL) and decreased oral total clearance (105.1 vs 74.4 L/h) only of S-(−)-fexofenadine, whereas the renal clearance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(−)-fexofenadine is influenced by fluoxetine to a greater extent that the R-(+)-fexofenadine. However, the transplacental transfer of fexofenadine is low (~16%), non-enantioselective and non-influenced by fluoxetine. Conclusions A single oral dose of 40 mg fluoxetine inhibited the intestinal P-gp mediated transport of S-(−)-fexofenadine to a greater extent than R-(+)-fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine.
Key points • P-glycoprotein (P-gp) is a drug transporter expressed in several organs, including intestine and placenta, and it is crucial in the enantioselective pharmacokinetics of fexofenadine. Then, the P-gp inhibitor fluoxetine could affect the maternal-fetal pharmacokinetics of fexofenadine enantiomers. • The specific P-gp inhibitor fluoxetine affected the intestinal P-gp mediated transport of S-(−)-fexofenadine to a greater extent than R-(+)fexofenadine in parturient women. However, the placental P-gp did not discriminate fexofenadine enantiomers and was not inhibited by fluoxetine. • This study contributes with the evaluation of the efficacy and safety of fexofenadine enantiomers administered during pregnancy and shows that enantioselective pharmacokinetics should be evaluated for other d
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