TY - JOUR T1 - Antibiotics-Induced Depletion of Rat Microbiota Induces Changes in the Expression of Host Drug-Processing Genes and Pharmacokinetic Behaviors of CYPs Probe Drugs JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 509 LP - 520 DO - 10.1124/dmd.122.001173 VL - 51 IS - 4 AU - Haijun Yang AU - Yanjuan Zhang AU - Rong Zhou AU - Tianyuan Wu AU - Peng Zhu AU - Yujie Liu AU - Jian Zhou AU - Yalan Xiong AU - Yanling Xiong AU - Honghao Zhou AU - Wei Zhang AU - Yan Shu AU - Xiong Li AU - Qing Li Y1 - 2023/04/01 UR - http://dmd.aspetjournals.org/content/51/4/509.abstract N2 - The metabolism of exogenous substances is affected by the gut microbiota, and the relationship between them has become a hot topic. However, the mechanisms by which the microbiota regulates drug metabolism have not been clearly defined. This study characterizes the expression profiles of host drug-processing genes (DPGs) in antibiotics-treated rats by using an unbias quantitative RNA-sequencing method and investigates the effects of antibiotics-induced depletion of rat microbiota on the pharmacokinetic behaviors of cytochrome P450s (CYPs) probe drugs, and bile acids metabolism by ultra-performance liquid chromatography-tandem mass spectrometry. Our results show that antibiotics treatments altered the mRNA expressions of 112 DPGs in the liver and jejunum of rats. The mRNA levels of CYP2A1, CYP2C11, CYP2C13, CYP2D, CYP2E1, and CYP3A of CYP family members were significantly downregulated in antibiotics-treated rats. Furthermore, antibiotics treatments also resulted in a significant decrease in the protein expressions and enzyme activities of CYP3A1 and CYP2E1 in rat liver. Pharmacokinetic results showed that, except for tolbutamide, antibiotics treatments significantly altered the pharmacokinetic behaviors of phenacetin, omeprazole, metoprolol, chlorzoxazone, and midazolam. In conclusion, the presence of stable, complex, and diverse gut microbiota plays a significant role in regulating the expression of host DPGs, which could contribute to some individual differences in pharmacokinetics.SIGNIFICANCE STATEMENT This study investigated how the depletion of rat microbiota by antibiotics treatments influences the expression profiles of host DPGs and the pharmacokinetic behaviors of CYPs probe drugs. Combined with previous studies in germ-free mice, this study will improve the understanding of the role of gut microbiota in drug metabolism and contribute to the understanding of individual differences in the pharmacokinetics of some drugs. ER -