Interrelationship between substrates and inhibitors of human CYP3A and P-glycoprotein.
Article Details
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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
Drug Transporter Kind Organism Pharmacological Action Actions Amiodarone P-glycoprotein 1 Protein Humans UnknownInhibitorInducerDetails Debrisoquine P-glycoprotein 1 Protein Humans UnknownSubstrateDetails Hydrocortisone P-glycoprotein 1 Protein Humans UnknownSubstrateInducerDetails Hydrocortisone aceponate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone acetate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone butyrate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone cypionate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone phosphate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone probutate P-glycoprotein 1 Protein Humans UnknownNot Available Details Hydrocortisone valerate P-glycoprotein 1 Protein Humans UnknownNot Available Details Lovastatin P-glycoprotein 1 Protein Humans UnknownInhibitorDetails Terfenadine P-glycoprotein 1 Protein Humans UnknownInhibitorDetails - Drug Interactions
Drugs Interaction Integrate drug-drug
interactions in your softwareAcetyldigitoxinErythromycin The serum concentration of Acetyldigitoxin can be increased when it is combined with Erythromycin. AcetyldigitoxinAzithromycin The serum concentration of Acetyldigitoxin can be increased when it is combined with Azithromycin. AcetyldigitoxinSirolimus The serum concentration of Acetyldigitoxin can be increased when it is combined with Sirolimus. AcetyldigitoxinDirithromycin The serum concentration of Acetyldigitoxin can be increased when it is combined with Dirithromycin. AcetyldigitoxinTelithromycin The serum concentration of Acetyldigitoxin can be increased when it is combined with Telithromycin.