Leonardo Pinto1,2, Priya Bapat3,4, Fernanda de Lima Moreira5, Angelika Lubetsky3, Ricardo de Carvalho Cavalli6, Howard Berger7, Vera Lucia Lanchote5, Gideon Koren8,9. 1. Department of Clinical Analysis, Food Science and Toxicology School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. leonardopinto84@gmail.com. 2. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada. leonardopinto84@gmail.com. 3. Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Ontario, Canada. 4. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. 5. Department of Clinical Analysis, Food Science and Toxicology School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. 6. Department of Obstetrics and Gynecology School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil. 7. Department of Obstetrics and Gynecology, St. Michael's Hospital, Toronto, Ontario, Canada. 8. Adelson Faculty of Medicine, Ariel University, Ariel, Israel. 9. Motherisk Israel Program, Zerifn, Israel.
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.
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.
Entities:
Keywords:
drug transporters; fexofenadine; fluoxetine; placenta; pregnancy
Authors: Aizati N A Daud; Jorieke E H Bergman; Marian K Bakker; Hao Wang; Wilhelmina S Kerstjens-Frederikse; Hermien E K de Walle; Henk Groen; Jens H J Bos; Eelko Hak; Bob Wilffert Journal: Drug Saf Date: 2015-07 Impact factor: 5.606
Authors: Aizati N A Daud; Jorieke E H Bergman; Monika P Oktora; Wilhelmina S Kerstjens-Frederikse; Henk Groen; Jens H Bos; Eelko Hak; Bob Wilffert Journal: PLoS One Date: 2017-03-13 Impact factor: 3.240