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• W2795919799 abstract "Abstract Rifampin is a pleiotropic inducer of multiple drug metabolizing enzymes and transporters. This work utilized a global approach to evaluate rifampin effects on conjugating enzyme gene expression with relevance to human xeno‐ and endo‐biotic metabolism. Primary human hepatocytes from 7 subjects were treated with rifampin (10 μmol/L, 24 hours). Standard methods for RNA ‐seq library construction, EZB ead preparation, and NextGen sequencing were used to measure UDP‐glucuronosyl transferase UGT , sulfonyltransferase SULT , N acetyltransferase NAT , and glutathione‐S‐transferase GST mRNA expression compared to vehicle control (0.01% Me OH ). Rifampin‐induced (>1.25‐fold) mRNA expression of 13 clinically important phase II drug metabolizing genes and repressed (>1.25‐fold) the expression of 3 genes ( P < .05). Rifampin‐induced mi RNA expression changes correlated with mRNA changes and mi RNA s were identified that may modulate conjugating enzyme expression. NAT 2 gene expression was most strongly repressed (1.3‐fold) by rifampin while UGT 1A4 and UGT 1A1 genes were most strongly induced (7.9‐ and 4.8‐fold, respectively). Physiologically based pharmacokinetic modeling ( PBPK ) was used to simulate the clinical consequences of rifampin induction of CYP 3A4‐ and UGT 1A4‐mediated midazolam metabolism. Simulations evaluating isolated UGT 1A4 induction predicted increased midazolam N‐glucuronide exposure (~4‐fold) with minimal reductions in parent midazolam exposure (~10%). Simulations accounting for simultaneous induction of both CYP 3A4 and UGT 1A4 predicted a ~10‐fold decrease in parent midazolam exposure with only a ~2‐fold decrease in midazolam N‐glucuronide metabolite exposure. These data reveal differential effects of rifampin on the human conjugating enzyme transcriptome and potential associations with mi RNA s that form the basis for future mechanistic studies to elucidate the interplay of conjugating enzyme regulatory elements." @default.
• W2795919799 created "2018-04-13" @default.
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• W2795919799 date "2018-03-26" @default.
• W2795919799 modified "2023-10-18" @default.
• W2795919799 title "Rifampin modulation of xeno- and endobiotic conjugating enzyme mRNA expression and associated microRNAs in human hepatocytes" @default.
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• W2795919799 doi "https://doi.org/10.1002/prp2.386" @default.
• W2795919799 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/5869567" @default.
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