Interaction of cytochrome P450 3A inhibitors with P-glycoprotein

Détails

ID Serval
serval:BIB_4158BB8D95B8
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Interaction of cytochrome P450 3A inhibitors with P-glycoprotein
Périodique
Journal of Pharmacology and Experimental Therapeutics
Auteur(s)
Yasuda  K., Lan  L. B., Sanglard  D., Furuya  K., Schuetz  J. D., Schuetz  E. G.
ISSN
0022-3565 (Print)
Statut éditorial
Publié
Date de publication
10/2002
Volume
303
Numéro
1
Pages
323-32
Notes
Journal Article
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.
Mots-clé
Animals *Aryl Hydrocarbon Hydroxylases Biological Transport Cell Line Cells, Cultured Cytochrome P-450 CYP3A Cytochrome P-450 Enzyme System/antagonists & inhibitors/*metabolism Dihydroergocryptine/*pharmacokinetics Drug Interactions Enzyme Inhibitors/*pharmacology Fluconazole/*pharmacokinetics Humans Mice Mice, Knockout Microsomes, Liver/enzymology Oxidoreductases, N-Demethylating/antagonists & inhibitors/*metabolism P-Glycoprotein/antagonists & inhibitors/deficiency/genetics/*metabolism Recombinant Proteins/antagonists & inhibitors/metabolism Reserpine/*pharmacokinetics Swine Tissue Distribution Transfection Vinblastine/*pharmacokinetics
Pubmed
Web of science
Création de la notice
25/01/2008 15:40
Dernière modification de la notice
03/03/2018 16:32
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