Antibiotics-Induced Depletion of Rat Microbiota Induces Changes in the Expression of Host Drug-Processing Genes and Pharmacokinetic Behaviors of CYPs Probe Drugs.

Haijun Yang Yanjuan Zhang Rong Zhou Tianyuan Wu Peng Zhu Yujie Liu Jian Zhou Yalan Xiong Yanling Xiong Honghao Zhou Wei Zhang Yan Shu Xiong Li Qing Li

Drug Metab Dispos

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, China (H.Y., Y.Z., R.Z., T.W., P.Z., Y.L., J.Z., Yalan X., Yanling X., H.Z., W.Z., Q.L.); Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University, Changsha, China (H.Y., Y.Z., R.Z., T.W., P.Z., Y.L., J.Z., Yalan X., Yanling X., H.Z., W.Z., Q.L.); Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, China (H.Y., Y.Z., R.Z., T.W., P.Z., Y.L., J.Z., Yalan X., Yanling X., H.Z., W.Z., X.L., Q.L.); National Clinical Research Center for Geriatric Disorders, Changsha, China (H.Y., Y.Z., R.Z., T.W., P.Z., Y.L., J.Z., Yalan X., Yanling X., H.Z., W.Z., Q.L.); Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland at Baltimore, Maryland (Y.S.); and Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China (X.L.)

Published: April 2023

* It found that antibiotics significantly altered the expression of 112 DPGs and affected the activity of cytochrome P450 enzymes, which are crucial for drug metabolism.
* The research suggests that the diversity of gut microbiota plays an important role in individual differences in how drugs are processed, enhancing our understanding of drug metabolism.

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 , , , , , and 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 and 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.

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http://dx.doi.org/10.1124/dmd.122.001173	DOI Listing

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