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

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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

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Cefradine	Cytochrome P450 3A4	Protein	Humans	Unknown	Inducer	Details
Dicloxacillin	Cytochrome P450 3A4	Protein	Humans	Unknown	Inducer	Details
Griseofulvin	Cytochrome P450 3A4	Protein	Humans	Unknown	Inducer	Details
Nafcillin	Cytochrome P450 3A4	Protein	Humans	Unknown	Inducer	Details

Drug Interactions

Drugs	Interaction
Integrate drug-drug interactions in your software
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.

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Cefaclor	Approved	CYP3A4	1576	upregulated	Cefaclor results in increased expression of CYP3A4 mRNA	7q22.1
Cefadroxil	Approved Vet Approved Withdrawn	CYP3A4	1576	upregulated	Cefadroxil results in increased expression of CYP3A4 mRNA	7q22.1
Clindamycin	Approved Vet Approved	CYP3A4	1576	upregulated	Clindamycin results in increased expression of CYP3A4 mRNA	7q22.1
Dicloxacillin	Approved Investigational Vet Approved	CYP3A4	1576	upregulated	Dicloxacillin results in increased expression of CYP3A4 mRNA	7q22.1
Erythromycin	Approved Investigational Vet Approved	CYP3A4	1576	upregulated	Erythromycin results in increased expression of CYP3A4 mRNA	7q22.1
Griseofulvin	Approved Investigational Vet Approved	CYP3A4	1576	upregulated	Griseofulvin results in increased expression of CYP3A4 mRNA	7q22.1
Nafcillin	Approved Investigational	CYP3A4	1576	upregulated	Nafcillin results in increased expression of CYP3A4 mRNA	7q22.1
Phenoxymethylpenicillin	Approved Vet Approved	CYP3A4	1576	upregulated	Penicillin V results in increased expression of CYP3A4 mRNA	7q22.1
Rifampicin	Approved	CYP3A4	1576	upregulated	Rifampin results in increased expression of CYP3A4 mRNA	7q22.1
Sulfisoxazole	Approved Vet Approved	CYP3A4	1576	upregulated	Sulfisoxazole results in increased expression of CYP3A4 mRNA	7q22.1
Tetracycline	Approved Vet Approved Withdrawn	CYP3A4	1576	upregulated	Tetracycline results in increased expression of CYP3A4 mRNA	7q22.1
Troleandomycin	Approved	CYP3A4	1576	upregulated	Troleandomycin results in increased expression of CYP3A4 mRNA	7q22.1