Chiral Transplacental Pharmacokinetics of Fexofenadine: Impact of P-Glycoprotein Inhibitor Fluoxetine Using the Human Placental Perfusion Model.
ATP Binding Cassette Transporter, Subfamily B
/ antagonists & inhibitors
Area Under Curve
Drug Interactions
Female
Fluoxetine
/ administration & dosage
Histamine H1 Antagonists, Non-Sedating
/ administration & dosage
Humans
Maternal-Fetal Exchange
/ drug effects
Perfusion
/ instrumentation
Placenta
/ metabolism
Pregnancy
Pregnancy Complications
/ drug therapy
Stereoisomerism
Terfenadine
/ administration & dosage
drug transporters
fexofenadine
fluoxetine
placenta
pregnancy
Journal
Pharmaceutical research
ISSN: 1573-904X
Titre abrégé: Pharm Res
Pays: United States
ID NLM: 8406521
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
14
01
2021
accepted:
23
03
2021
pubmed:
8
4
2021
medline:
9
11
2021
entrez:
7
4
2021
Statut:
ppublish
Résumé
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. 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. 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 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.
Identifiants
pubmed: 33825113
doi: 10.1007/s11095-021-03035-7
pii: 10.1007/s11095-021-03035-7
doi:
Substances chimiques
ABCB1 protein, human
0
ATP Binding Cassette Transporter, Subfamily B
0
Histamine H1 Antagonists, Non-Sedating
0
Fluoxetine
01K63SUP8D
Terfenadine
7BA5G9Y06Q
fexofenadine
E6582LOH6V
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
647-655Subventions
Organisme : Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
ID : BEX6119/13-1
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