EXPLORING HOST METABOTYPE-MICROBIOTA INTERACTION: A SILENT PHENOTYPE IN DRUG DISPOSITION AND TOXICITY

Abstract

THE SUPERORGANISMIC NATURE OF THE HUMAN HOST UNDERSCORES THE IMPORTANCE OF GUT MICROBIOTA AND ITS ASSOCIATED METABOLIC ACTIVITIES ON INTER-INDIVIDUAL RESPONSES TO PHARMACOTHERAPY. TACRINE, AN ALZHEIMER?S DISEASE DRUG, EXHIBITS SIGNIFICANT INTER-INDIVIDUAL VARIABILITY IN ITS TOXICOKINETICS OF YET UNKNOWN ETIOLOGY. HERE, WE FOUND THAT GUT BACTERIA INFLUENCES THE TOXICOKINETICS OF TACRINE IN LISTER-HOODED RATS THROUGH MODULATING INTESTINAL ?-GLUCURONIDASE ACTIVITIES. PHARMACOKINETICS DEMONSTRATED A 3.3-FOLD HIGHER SYSTEMIC EXPOSURE OF TACRINE AND DOUBLE-CMAX PHENOMENON IN EXTREME RESPONDERS TO TACRINE-INDUCED TRANSAMINITIS, REVEALING ENHANCED ENTEROHEPATIC RECIRCULATION OF DEGLUCURONIDATED TACRINE, NOT ATTRIBUTABLE TO VARIATION IN HOST DISPOSITION GENE EXPRESSION. METABONOMICS UNCOVERED METABOLITES OF MICROBIAL AND CO-MICROBIAL ORIGINS THAT DEFINED TACRINE-INDUCED TRANSAMINITIS. METAGENOMICS FURTHER DELINEATED GREATER DEGLUCURONIDATION PROPENSITIES IN EXTREME RESPONDERS, BASED ON DIFFEREN