Gut microbiota and host Cyp450s co-contribute to pharmacokinetic variability in mice with non-alcoholic steatohepatitis: Effects vary from drug to drug.

J Adv Res

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China; Institute of Clinical Pharmacology, Central South University, Changsha, Hunan, China; Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of Education, Changsha, Hunan, China; National Clinical Research Center for Geriatric Disorders, Changsha, Hunan, China. Electronic address:

Published: July 2022

Introduction: Pharmacokinetic variability in disease state is common in clinical practice, but its underlying mechanism remains unclear. Recently, gut microbiota has been considered to be pharmacokinetically equivalent to the host liver. Although some studies have explored the roles of gut microbiota and host Cyp450s in drug pharmacokinetics, few have explored their effects on pharmacokinetic variability, especially in disease states.

Objectives: In this study, we aim to investigate the effects of gut microbiota and host Cyp450s on pharmacokinetic variability in mice with non-alcoholic steatohepatitis (NASH), and to elucidate the contribution of gut microbiota and host Cyp450s to pharmacokinetic variability in this setting.

Methods: The pharmacokinetic variability of mice with NASH was explored under intragastric and intravenous administrations of a cocktail mixture of omeprazole, phenacetin, midazolam, tolbutamide, chlorzoxazone, and metoprolol, after which the results were compared with those obtained from the control group. Thereafter, the pharmacokinetic variabilities of all drugs and their relations to the changes in gut microbiota and host Cyp450s were compared and analyzed.

Results: The exposures of all drugs, except metoprolol, significantly increased in the NASH group under intragastric administration. However, no significant increase in the exposure of all drugs, except tolbutamide, was observed in the NASH group under intravenous administration. The pharmacokinetic variabilities of phenacetin, midazolam, omeprazole, and chlorzoxazone were mainly associated with decreased elimination activity in the gut microbiota. By contrast, the pharmacokinetic variability of tolbutamide was mainly related to the change in the host Cyp2c65. Notably, gut microbiota and host Cyp450s exerted minimal effects on the pharmacokinetic variability of metoprolol.

Conclusion: Gut microbiota and host Cyp450s co-contribute to the pharmacokinetic variability in mice with NASH, and the degree of contribution varies from drug to drug. The present findings provide new insights into the explanation of pharmacokinetic variability in disease states.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9263650PMC
http://dx.doi.org/10.1016/j.jare.2021.10.004DOI Listing

Publication Analysis

Top Keywords

pharmacokinetic variability
40
gut microbiota
36
microbiota host
28
host cyp450s
28
variability mice
16
pharmacokinetic
12
variability disease
12
variability
10
gut
9
host
9

Similar Publications

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!