Background and Objective
Fluoxetine, antidepressant widely-used during pregnancy, is a selective inhibitor for P-glycoprotein (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 maternal-fetal pharmacokinetics of fexofenadine.
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.
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.
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.
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ACKNOWLEDGMENTS AND DISCLOSURES
The authors thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) for financial support. The authors declare no conflict of interest. Informed consent was obtained from all individual participants included in the study.
This study was funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP).
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• 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 drugs substrates of P-gp during gestation, considering that fluoxetine is a common antidepressant used during pregnancy.
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Pinto, L., Moreira, F.d., Nardotto, G.H.B. et al. Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics. Pharm Res 37, 131 (2020). https://doi.org/10.1007/s11095-020-02854-4