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Hepatocytic transcriptional signatures predict comparative drug interaction potential of rifamycin antibiotics.

Abstract：

:Current strategies to treat tuberculosis (TB) and co-morbidities involve multidrug combination therapies. Rifamycin antibiotics are a key component of TB therapy and a common source of drug-drug interactions (DDIs) due to induction of drug metabolizing enzymes (DMEs). Management of rifamycin DDIs are complex, particularly in patients with co-morbidities, and differences in DDI potential between rifamycin antibiotics are not well established. DME profiles induced in response to tuberculosis antibiotics (rifampin, rifabutin and rifapentine) were compared in primary human hepatocytes. We identified rifamycin induced DMEs, cytochrome P450 (CYP) 2C8/3A4/3A5, SULT2A, and UGT1A4/1A5 and predicted lower DDIs of rifapentine with 58 clinical drugs used to treat co-morbidities in TB patients. Transcriptional networks and upstream regulator analyses showed FOXA3, HNF4α, NR1I2, NR1I3, NR3C1 and RXRα as key transcriptional regulators of rifamycin induced DMEs. Our study findings are an important resource to design effective medication regimens to treat common co-conditions in TB patients.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Dyavar SR,Mykris TM,Winchester LC,Scarsi KK,Fletcher CV,Podany AT

doi

10.1038/s41598-020-69228-z

subject

Has Abstract

pub_date

2020-07-28 00:00:00

pages

12565

issue

1

issn

2045-2322

pii

10.1038/s41598-020-69228-z

journal_volume

10

pub_type

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