Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.

Article Details

Citation

Kim RB, Wandel C, Leake B, Cvetkovic M, Fromm MF, Dempsey PJ, Roden MM, Belas F, Chaudhary AK, Roden DM, Wood AJ, Wilkinson GR

Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.

Pharm Res. 1999 Mar;16(3):408-14.

PubMed ID
10213372 [ View in PubMed
]
Abstract

PURPOSE: CYP3A and P-gp both function to reduce the intracellular concentration of drug substrates, one by metabolism and the other by transmembrane efflux. Moreover, it has been serendipitously noted that the two proteins have many common substrates and inhibitors. In order to test this notion more fully, systematic studies were undertaken to determine the P-gp-mediated transport and inhibitory characteristics of prototypical CYP substrates. METHODS: L-MDR1, LLC-PK1, and Caco-2 cells were used to evaluate established CYP substrates as potential P-gp substrates and inhibitors in vitro, and mdr1a deficient mice were used to assess the in vivo relevance of P-gp-mediated transport. RESULTS: Some (terfenadine, erythromycin and lovastatin) but not all (nifedipine and midazolam) CYP3A substrates were found to be P-gp substrates. Except for debrisoquine, none of the prototypical substrates of other common human CYP isoforms were transported by P-gp. Studies in mdr1a disrupted mice confirmed that erythromycin was a P-gp substrate but the CYP3A-inhibitor ketoconazole was not. In addition, CYP3A substrates and inhibitors varied widely in their ability to inhibit the P-gp-mediated transport of digoxin. CONCLUSIONS: These results indicate that the overlap in substrate specificities of CYP3A and P-gp appears to be fortuitous rather than indicative of a more fundamental relationship.

DrugBank Data that Cites this Article

Drug Transporters
DrugTransporterKindOrganismPharmacological ActionActions
AmiodaroneP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Inducer
Details
DebrisoquineP-glycoprotein 1ProteinHumans
Unknown
Substrate
Details
HydrocortisoneP-glycoprotein 1ProteinHumans
Unknown
Substrate
Inducer
Details
Hydrocortisone aceponateP-glycoprotein 1ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone acetateP-glycoprotein 1ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone butyrateP-glycoprotein 1ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone cypionateP-glycoprotein 1ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone phosphateP-glycoprotein 1ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone probutateP-glycoprotein 1ProteinHumans
Unknown
Not AvailableDetails
Hydrocortisone valerateP-glycoprotein 1ProteinHumans
Unknown
Not AvailableDetails
LovastatinP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
TerfenadineP-glycoprotein 1ProteinHumans
Unknown
Inhibitor
Details
Drug Interactions
DrugsInteraction
Acetyldigitoxin
Erythromycin
The serum concentration of Acetyldigitoxin can be increased when it is combined with Erythromycin.
Acetyldigitoxin
Azithromycin
The serum concentration of Acetyldigitoxin can be increased when it is combined with Azithromycin.
Acetyldigitoxin
Sirolimus
The serum concentration of Acetyldigitoxin can be increased when it is combined with Sirolimus.
Acetyldigitoxin
Dirithromycin
The serum concentration of Acetyldigitoxin can be increased when it is combined with Dirithromycin.
Acetyldigitoxin
Telithromycin
The serum concentration of Acetyldigitoxin can be increased when it is combined with Telithromycin.
Acetyldigitoxin
Candicidin
The serum concentration of Acetyldigitoxin can be increased when it is combined with Candicidin.
Acetyldigitoxin
Clarithromycin
The serum concentration of Acetyldigitoxin can be increased when it is combined with Clarithromycin.
Acetyldigitoxin
Josamycin
The serum concentration of Acetyldigitoxin can be increased when it is combined with Josamycin.
Acetyldigitoxin
Everolimus
The serum concentration of Acetyldigitoxin can be increased when it is combined with Everolimus.
Acetyldigitoxin
Epothilone D
The serum concentration of Acetyldigitoxin can be increased when it is combined with Epothilone D.
Interactions
Improve patient outcomes
Build effective decision support tools with the industry’s most comprehensive drug-drug interaction checker.
Learn more