RT Journal Article SR Electronic 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 FD American Society for Pharmacology and Experimental Therapeutics SP DMD-AR-2022-001173 DO 10.1124/dmd.122.001173 A1 Yang, Haijun A1 Zhang, Yanjuan A1 Zhou, Rong A1 Wu, Tianyuan A1 Zhu, Peng A1 Liu, Yujie A1 Zhou, Jian A1 Xiong, Yalan A1 Xiong, Yanling A1 Zhou, Honghao A1 Zhang, Wei A1 Shu, Yan A1 Li, Xiong A1 Li, Qing YR 2023 UL http://dmd.aspetjournals.org/content/early/2023/01/06/dmd.122.001173.abstract AB 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-Seq 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 (BAs) metabolism by UPLC-MS/MS. 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 probably 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 (GF) 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.