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Tytuł:
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Chiral Discrimination of P-glycoprotein in Parturient Women: Effect of Fluoxetine on Maternal-Fetal Fexofenadine Pharmacokinetics.
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Autorzy:
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Pinto L; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Moreira FL; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Nardotto GHB; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Cavalli RC; Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Moisés ECD; Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Duarte G; Departamento de Obstetrícia e Ginecologia, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
Lanchote VL; Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil. .
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Źródło:
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Pharmaceutical research [Pharm Res] 2020 Jun 17; Vol. 37 (7), pp. 131. Date of Electronic Publication: 2020 Jun 17.
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Typ publikacji:
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Journal Article
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Język:
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English
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Imprint Name(s):
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Publication: 1999- : New York, NY : Kluwer Academic/Plenum Publishers
Original Publication: Stuttgart ; New York : Thieme, c1984-
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MeSH Terms:
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Parturition*
Antidepressive Agents, Second-Generation/*administration & dosage
Fluoxetine/*administration & dosage
Histamine H1 Antagonists, Non-Sedating/*pharmacokinetics
Intestinal Absorption/*drug effects
Intestinal Mucosa/*drug effects
Terfenadine/*analogs & derivatives
ATP Binding Cassette Transporter, Subfamily B/antagonists & inhibitors ; ATP Binding Cassette Transporter, Subfamily B/metabolism ; Adult ; Antidepressive Agents, Second-Generation/adverse effects ; Case-Control Studies ; Drug Interactions ; Female ; Fetal Blood/metabolism ; Fluoxetine/adverse effects ; Histamine H1 Antagonists, Non-Sedating/administration & dosage ; Histamine H1 Antagonists, Non-Sedating/blood ; Humans ; Intestinal Mucosa/metabolism ; Maternal-Fetal Exchange ; Placental Circulation ; Pregnancy ; Terfenadine/administration & dosage ; Terfenadine/blood ; Terfenadine/pharmacokinetics ; Young Adult
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Grant Information:
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303142/2019-7 Conselho Nacional de Desenvolvimento Científico e Tecnológico
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Contributed Indexing:
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Keywords: CPKA-D-20-00095; P-gp; fexofenadine; fluoxetine; pharmacokinetics; pregnancy
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Substance Nomenclature:
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0 (ABCB1 protein, human)
0 (ATP Binding Cassette Transporter, Subfamily B)
0 (Antidepressive Agents, Second-Generation)
0 (Histamine H1 Antagonists, Non-Sedating)
01K63SUP8D (Fluoxetine)
7BA5G9Y06Q (Terfenadine)
E6582LOH6V (fexofenadine)
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Entry Date(s):
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Date Created: 20200620 Date Completed: 20210422 Latest Revision: 20210422
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Update Code:
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20240105
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DOI:
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10.1007/s11095-020-02854-4
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PMID:
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32557079
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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.
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 (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 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.