Titre
Interaction of cytochrome P450 3A inhibitors with P-glycoprotein
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Auteur(s)
Yasuda, K.
Auteure/Auteur
Lan, L. B.
Auteure/Auteur
Sanglard, D.
Auteure/Auteur
Furuya, K.
Auteure/Auteur
Schuetz, J. D.
Auteure/Auteur
Schuetz, E. G.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
0022-3565
Statut éditorial
Publié
Date de publication
2002-10
Volume
303
Numéro
1
Première page
323
Dernière page/numéro d’article
32
Notes
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Oct
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S. --- Old month value: Oct
Résumé
Many clinically important drug interactions occur due to inhibition of human liver cytochrome P450 3A (CYP3A) metabolism. The drug efflux pump P-glycoprotein (Pgp) can be an additional locus contributing to these drug interactions because there is overlap in drugs that are substrates for both proteins. We screened a number of CYP3A inhibitors (macrolide antibiotics, azole antifungals, and ergotpeptides) for their ability to interact with Pgp, compared with prototypical Pgp inhibitors. We used cell lines expressing human, mouse, and rat mdr1 genes. Pgp antagonism was defined by interactions of the drugs with four cell lines (LLC-PK1, L-MDR1, L-mdr1a, and L-mdr1b) using a microfluorometric calcein-AM assay and characterized for their inhibitor constant (K(i)) toward calcein-AM. The compounds were further defined for their ability to inhibit MDR1 by their effect on vinblastine accumulation into L-MDR1 cells. Representative compounds from each class of drugs were further tested as Pgp substrates, defined by the ability of human Pgp or mouse mdr1a/Pgp to transport them across a polarized kidney epithelial cell in vitro. These same compounds were administered radiolabeled in vivo to mdr1a (+/+) and (-/-) mice and the distribution of radioactivity compared. The results are summarized as follows: 1) Some drug interactions with Pgp were substrate- and/or assay-dependent. 2) Ergot alkaloids were identified as a class of MDR1/Pgp chemosensitizers. 3) The Ergot alkaloids revealed species differences in the structure-activity relationships for inhibition of Pgp. Simultaneous inhibition of Pgp by many CYP3A inhibitors contributes to human variation in the extent of drug-drug interactions.
Sujets
PID Serval
serval:BIB_4158BB8D95B8
PMID
Date de création
2008-01-25T13:40:33.911Z
Date de création dans IRIS
2025-05-20T17:30:50Z