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Research ArticleArticle

A Comprehensive in Vitro and in Silico Analysis of Antibiotics That Activate Pregnane X Receptor and Induce CYP3A4 in Liver and Intestine

Kazuto Yasuda, Aarati Ranade, Raman Venkataramanan, Stephen Strom, Jonathan Chupka, Sean Ekins, Erin Schuetz and Kenneth Bachmann
Drug Metabolism and Disposition August 2008, 36 (8) 1689-1697; DOI: https://doi.org/10.1124/dmd.108.020701
Kazuto Yasuda
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Aarati Ranade
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Raman Venkataramanan
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Stephen Strom
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Jonathan Chupka
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Sean Ekins
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Erin Schuetz
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Kenneth Bachmann
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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 6β-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 (≥7-fold) by dicloxacillin, tetracycline, clindamycin, griseofulvin, and (≥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.

Footnotes

  • This work was supported in part by National Institutes of Health Grant GM60346, National Institutes of Health P30 CA21765 Cancer Center Support Grant, and the American Lebanese Syrian Associated Charities.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.020701.

  • ABBREVIATIONS: PXR, pregnane X receptor; h, human; OC, oral contraceptive; RIF, rifampin; PNCV, penicillin V; NFC, nafcillin; DXC, dicloxacillin; AXC, amoxicillin; APC, ampicillin; CFDX, cefadroxil; CPRD, cephradine; CPLX, cephalexin; CFCL, cefaclor; CFXM, cefuroxime; TCL, tetracycline; DXCL, doxycycline; MCL, minocycline; DCCL, demeclocycline; SXZ, sulfisoxazole; SMXZ, sulfamethoxazole; ERM, erythromycin; TAO, triacetyloleandomycin; GSF, griseofulvin; CMC, clindamycin; DMSO, dimethyl sulfoxide; RIS, relative induction score(s); PCR, polymerase chain reaction; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HH, human hepatocytes; CT, control.

  • ↵ Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

    • Received January 31, 2008.
    • Accepted May 19, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (8)
Drug Metabolism and Disposition
Vol. 36, Issue 8
1 Aug 2008
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Research ArticleArticle

A Comprehensive in Vitro and in Silico Analysis of Antibiotics That Activate Pregnane X Receptor and Induce CYP3A4 in Liver and Intestine

Kazuto Yasuda, Aarati Ranade, Raman Venkataramanan, Stephen Strom, Jonathan Chupka, Sean Ekins, Erin Schuetz and Kenneth Bachmann
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1689-1697; DOI: https://doi.org/10.1124/dmd.108.020701

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Research ArticleArticle

A Comprehensive in Vitro and in Silico Analysis of Antibiotics That Activate Pregnane X Receptor and Induce CYP3A4 in Liver and Intestine

Kazuto Yasuda, Aarati Ranade, Raman Venkataramanan, Stephen Strom, Jonathan Chupka, Sean Ekins, Erin Schuetz and Kenneth Bachmann
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1689-1697; DOI: https://doi.org/10.1124/dmd.108.020701
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