Interaction of cytochrome P450 3A inhibitors with P-glycoprotein.
Article Details
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Yasuda K, Lan LB, Sanglard D, Furuya K, Schuetz JD, Schuetz EG
Interaction of cytochrome P450 3A inhibitors with P-glycoprotein.
J Pharmacol Exp Ther. 2002 Oct;303(1):323-32.
- PubMed ID
- 12235267 [ View in PubMed]
- Abstract
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.
DrugBank Data that Cites this Article
- Drug Transporters
Drug Transporter Kind Organism Pharmacological Action Actions Amiodarone ATP-dependent translocase ABCB1 Protein Humans UnknownInhibitorInducerDetails Bromocriptine ATP-dependent translocase ABCB1 Protein Humans UnknownSubstrateInhibitorDetails Dihydroergotamine ATP-dependent translocase ABCB1 Protein Humans UnknownInhibitorDetails Ergometrine ATP-dependent translocase ABCB1 Protein Humans UnknownInhibitorDetails Ergotamine ATP-dependent translocase ABCB1 Protein Humans UnknownInhibitorDetails Ketoconazole ATP-dependent translocase ABCB1 Protein Humans UnknownInhibitorDetails Miconazole ATP-dependent translocase ABCB1 Protein Humans UnknownInhibitorDetails Reserpine ATP-dependent translocase ABCB1 Protein Humans UnknownSubstrateInhibitorInducerDetails Troleandomycin ATP-dependent translocase ABCB1 Protein Humans UnknownInhibitorDetails