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 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 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 discrimina- tion of P-gp investigating the effect of fluoxetine on maternal- fetal 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 collect- ed up to 48 h after fexofenadine administration. At delivery, maternal-placental-fetal blood samples were collected. Results The maternal pharmacokinetics of fexofenadine was enantioselective (AUC 0–∞ R-(+)/S-(-) ~ 1.5) in both control and interaction groups. Fluoxetine increased AUC 0-∞ (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 clear- ance were reduced for both enantiomers, suggesting that the intestinal P-gp-mediated transport of S-(-)-fexofenadine is in- fluenced by fluoxetine to a greater extent that the R-(+)-fex- ofenadine. However, the transplacental transfer of fexofena- dine 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 wom- en. However, the placental P-gp did not discriminate fexofe- nadine enantiomers and was not inhibited by fluoxetine. KEY WORDS CPKA-D-20-00095 . fexofenadine . fluoxetine . pregnancy . pharmacokinetics . P-gp INTRODUCTION Clinical depression and anxiety occur in 6.5–12.9% and 21– 25% of women during pregnancy, respectively (1,2), and fluoxetine, a selective serotonin reuptake inhibitor (SSRI), is used for treatment of these conditions (3,4). Fluoxetine and its active metabolite, norfluoxetine, are chiral SSRI. Both S-(+)- and R-(-)-fluoxetine exhibit similar potencies (5–7), neverthe- less, S-(+)-norfluoxetine is 20 times more potent than R-(-)- norfluoxetine (8,9). Previous studies of our research group showed that maternal-fetal pharmacokinetics of fluoxetine and norfluoxetine is enantioselective (10). Some in vitro and in vivo reports regarding drug–drug interactions have shown that fluoxetine and its metabolite norfluoxetine are P-gp inhibitors (11–14). The fluoxetine administration increases 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 drugs sub- strates of P-gp during gestation, considering that fluoxetine is a common antidepressant used during pregnancy. * Vera Lucia Lanchote lanchote@fcfrp.usp.br 1 Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP , Brazil 2 Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP , Brazil Pharm Res (2020) 37:131 https://doi.org/10.1007/s11095-020-02854-4