Gut Microbiota Metabolize Etoposide to its Demethylated Product

Seminar given by Ashutosh Tripathi, Ph.D. Candidate

Advisor: Dr. Hyun-Young Jeong

Biopharmaceutical Sciences, UIC

Abstract: Etoposide is a first-line chemotherapeutic agent used for many different types of cancer. It has a narrow therapeutic index and exhibits high inter- and intra- individual variability in bioavailability. However, the major contributors to the variability remain unclear. The objective of this study is to examine the role of gut microbiota in etoposide disposition. Upon incubation of etoposide with mouse cecal contents and human stool samples, significant loss of etoposide was observed which was accompanied by appearance of new metabolite peak (M1) in HPLC-UV chromatogram. Subsequent isolation, purification, and structure elucidation of M1 revealed that M1 is O-demethylated product of etoposide (i.e., etoposide catechol). As compared to etoposide, M1 exhibited 3 to 5 fold lower cytotoxicity in cancer cells and comparable permeability across Caco-2 monolayer. When 48 commensal bacterial species in human gut were screened for M1 production, Eubacterium limosum was found to metabolize etoposide into M1. These results suggest gut microbiota-mediated metabolism as a previously unrecognized elimination route for etoposide, and this may potentially contribute to the low and variable etoposide exposure after oral dosing.