Compensatory Transition of Bile Acid Metabolism from Fecal Disposition of Secondary Bile Acids to Urinary Excretion of Primary Bile Acids Underlies Rifampicin-Induced Cholestasis in Beagle Dogs

Abstract

Drug induced cholestasis (DIC) is complexly associated with dysbiosis of the host-gut microbial cometabolism of bile acids (BAs). Murine animals are not suitable for transitional studies because the murine BA metabolism is quite different from human metabolism. In this work, the rifampicin (RFP) induced cholestasis was established in beagle dogs that have a humanlike BA profile to disclose how RFP affects the host-gut microbial cometabolism of BAs. The daily excretion of BA metabolites in urine and feces was extensively analyzed during cholestasis by quantitative BA profiling along the primary-secondary-tertiary axis. Oral midazolam clearance was also acquired to monitor the RFP-induced enterohepatic CYP3A activities because CYP3A is exclusively responsible for the tertiary oxidation of hydrophobic secondary BAs. RFP treatments caused a compensatory transition of the BA metabolism from the fecal disposition of secondary BAs to the urinary excretion of primary BAs in dogs, resulting in an infantile BA metabolism pattern recently disclosed in newborns. However, the tertiary BAs consistently constituted limitedly in the daily BA excretion, indicating that the detoxification role of the CYP3A catalyzed tertiary BA metabolism was not as strong as expected in this model. Multiple host-gut microbial factors might have contributed to the transition of the BA metabolism, such as inhibition of BA transporters, induction of liver-kidney interplaying detoxification mechanisms, and elimination of gut bacteria responsible for secondary BA production. Transitional studies involving more cholestatic drugs in preclinical animals with a humanlike BA profile and DIC patients may pave the way for understanding the complex mechanism of DIC in the era of metagenomics.