A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine.

Article Details

Citation

Yasuda K, Ranade A, Venkataramanan R, Strom S, Chupka J, Ekins S, Schuetz E, Bachmann K

A comprehensive in vitro and in silico analysis of antibiotics that activate pregnane X receptor and induce CYP3A4 in liver and intestine.

Drug Metab Dispos. 2008 Aug;36(8):1689-97. doi: 10.1124/dmd.108.020701. Epub 2008 May 27.

PubMed ID
18505790 [ View in PubMed
]
Abstract

We have investigated several in silico and in vitro methods to improve our ability to predict potential drug interactions of antibiotics. Our focus was to identify those antibiotics that activate pregnane X receptor (PXR) and induce CYP3A4 in human hepatocytes and intestinal cells. Human PXR activation was screened using reporter assays in HepG2 cells, kinetic measurements of PXR activation were made in DPX-2 cells, and induction of CYP3A4 expression and activity was verified by quantitative polymerase chain reaction, immunoblotting, and testosterone 6beta-hydroxylation in primary human hepatocytes and LS180 cells. We found that in HepG2 cells CYP3A4 transcription was activated strongly (> 10-fold) by rifampin and troleandomycin; moderately (> or = 7-fold) by dicloxacillin, tetracycline, clindamycin, griseofulvin, and (> or = 4-fold) erythromycin; and weakly (> 2.4-fold) by nafcillin, cefaclor, sulfisoxazole, and (> 2-fold) cefadroxil and penicillin V. Similar although not identical results were obtained in DPX-2 cells. CYP3A4 mRNA and protein expression were induced by these antibiotics to differing extents in both liver and intestinal cells. CYP3A4 activity was significantly increased by rifampin (9.7-fold), nafcillin and dicloxacillin (5.9-fold), and weakly induced (2-fold) by tetracycline, sufisoxazole, troleandomycin, and clindamycin. Multiple pharmacophore models and docking indicated a good fit for dicloxacillin and nafcillin in PXR. These results suggest that in vitro and in silico methods can help to prioritize and identify antibiotics that are most likely to reduce exposures of medications (such as oral contraceptive agents) which interact with enzymes and transporters regulated by PXR. In summary, nafcillin, dicloxacillin, cephradine, tetracycline, sulfixoxazole, erythromycin, clindamycin, and griseofulvin exhibit a clear propensity to induce CYP3A4 and warrant further clinical investigation.

DrugBank Data that Cites this Article

Drug Enzymes
DrugEnzymeKindOrganismPharmacological ActionActions
CefradineCytochrome P450 3A4ProteinHumans
Unknown
Inducer
Details
DicloxacillinCytochrome P450 3A4ProteinHumans
Unknown
Inducer
Details
GriseofulvinCytochrome P450 3A4ProteinHumans
Unknown
Inducer
Details
NafcillinCytochrome P450 3A4ProteinHumans
Unknown
Inducer
Details
Drug Interactions
DrugsInteraction
Cyclosporine
Griseofulvin
The serum concentration of Cyclosporine can be decreased when it is combined with Griseofulvin.
Cyproterone acetate
Piperacillin
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Piperacillin.
Cyproterone acetate
Ampicillin
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Ampicillin.
Cyproterone acetate
Phenoxymethylpenicillin
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Phenoxymethylpenicillin.
Cyproterone acetate
Carbenicillin
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Carbenicillin.
Cyproterone acetate
Oxacillin
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Oxacillin.
Cyproterone acetate
Hetacillin
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Hetacillin.
Cyproterone acetate
Benzylpenicilloyl polylysine
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Benzylpenicilloyl polylysine.
Cyproterone acetate
Mezlocillin
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Mezlocillin.
Cyproterone acetate
Cyclacillin
The therapeutic efficacy of Cyproterone acetate can be decreased when used in combination with Cyclacillin.
Interactions
Improve patient outcomes
Build effective decision support tools with the industry’s most comprehensive drug-drug interaction checker.
Learn more
Pharmaco-transcriptomics
DrugDrug GroupsGeneGene IDChangeInteractionChromosome
CefaclorApprovedCYP3A41576
upregulated
Cefaclor results in increased expression of CYP3A4 mRNA7q22.1
CefadroxilApproved Vet Approved WithdrawnCYP3A41576
upregulated
Cefadroxil results in increased expression of CYP3A4 mRNA7q22.1
ClindamycinApproved Vet ApprovedCYP3A41576
upregulated
Clindamycin results in increased expression of CYP3A4 mRNA7q22.1
DicloxacillinApproved Investigational Vet ApprovedCYP3A41576
upregulated
Dicloxacillin results in increased expression of CYP3A4 mRNA7q22.1
ErythromycinApproved Investigational Vet ApprovedCYP3A41576
upregulated
Erythromycin results in increased expression of CYP3A4 mRNA7q22.1
GriseofulvinApproved Investigational Vet ApprovedCYP3A41576
upregulated
Griseofulvin results in increased expression of CYP3A4 mRNA7q22.1
NafcillinApproved InvestigationalCYP3A41576
upregulated
Nafcillin results in increased expression of CYP3A4 mRNA7q22.1
PhenoxymethylpenicillinApproved Vet ApprovedCYP3A41576
upregulated
Penicillin V results in increased expression of CYP3A4 mRNA7q22.1
RifampicinApprovedCYP3A41576
upregulated
Rifampin results in increased expression of CYP3A4 mRNA7q22.1
SulfisoxazoleApproved Vet ApprovedCYP3A41576
upregulated
Sulfisoxazole results in increased expression of CYP3A4 mRNA7q22.1
TetracyclineApproved Vet ApprovedCYP3A41576
upregulated
Tetracycline results in increased expression of CYP3A4 mRNA7q22.1
TroleandomycinApprovedCYP3A41576
upregulated
Troleandomycin results in increased expression of CYP3A4 mRNA7q22.1