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Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model

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Abstract

Purpose

Fexofenadine is a well-identified in vivo probe substrate of P-glycoprotein (P-gp) and/or organic anion transporting polypeptide (OATP). This work aimed to investigate the transplacental pharmacokinetics of fexofenadine enantiomers with and without the selective P-gp inhibitor fluoxetine.

Methods

The chiral transplacental pharmacokinetics of fexofenadine-fluoxetine interaction was determined using the ex vivo human placenta perfusion model (n = 4). In the Control period, racemic fexofenadine (75 ng of each enantiomer/ml) was added in the maternal circuit. In the Interaction period, racemic fluoxetine (50 ng of each enantiomer/mL) and racemic fexofenadine (75 ng of each enantiomer/mL) were added to the maternal circulation. In both periods, maternal and fetal perfusate samples were taken over 90 min.

Results

The (S)-(−)- and (R)-(+)-fexofenadine fetal-to-maternal ratio values in Control and Interaction periods were similar (~0.18). The placental transfer rates were similar between (S)-(−)- and (R)-(+)-fexofenadine in both Control (0.0024 vs 0.0019 min−1) and Interaction (0.0019 vs 0.0021 min−1) periods. In both Control and Interaction periods, the enantiomeric fexofenadine ratios [R-(+)/S-(−)] were approximately 1.

Conclusions

Our study showed a low extent, slow rate of non-enantioselective placental transfer of fexofenadine enantiomers, indicating a limited fetal fexofenadine exposure mediated by placental P-gp and/or OATP2B1. The fluoxetine interaction did not affect the non-enantioselective transplacental transfer of fexofenadine. The ex vivo placental perfusion model accurately predicts in vivo placental transfer of fexofenadine enantiomers with remarkably similar values (~0.17), and thus estimates the limited fetal exposure.

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Data Availability

The data sets obtained and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

OATP:

Organic anion transporting polypeptide

P-gp:

P-glycoprotein

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Financial Support

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; BEX6119/13–1).

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Authors and Affiliations

  1. Department of Clinical Analysis, Food Science and Toxicology School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Leonardo Pinto, Fernanda de Lima Moreira & Vera Lucia Lanchote

  2. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada

    Leonardo Pinto, Priya Bapat & Angelika Lubetsky

  3. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    Priya Bapat

  4. Department of Obstetrics and Gynecology School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil

    Ricardo de Carvalho Cavalli

  5. Department of Obstetrics and Gynecology, St. Michael’s Hospital, Toronto, Ontario, Canada

    Howard Berger

  6. Adelson Faculty of Medicine, Ariel University, Ariel, Israel

    Gideon Koren

  7. Motherisk Israel Program, Zerifn, Israel

    Gideon Koren

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  1. Leonardo Pinto
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Correspondence to Leonardo Pinto.

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Pinto, L., Bapat, P., de Lima Moreira, F. et al. Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model. Pharm Res 38, 647–655 (2021). https://doi.org/10.1007/s11095-021-03035-7

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