Speaker
Description
Abstract
Background: Venetoclax (VEN) shows marked interindividual pharmacokinetic (PK) variability that may affect therapeutic response. As prolonged antibiotic exposure is common in hematologic malignancies and gut microbiota regulates bile acid–mediated solubilization of poorly water-soluble drugs, we investigated whether microbiota disruption alters VEN PK.
Methods: A pseudo-germ-free rat model was established using a clinically relevant antibiotic cocktail (ABX-c). Gut microbiota and bile acid profiles were characterized by metagenomics and targeted metabolomics. VEN PK was evaluated following oral administration. Correlation analyses, in vitro micellar solubilization assays, and an in vivo bile acid reconstitution experiment were performed to determine mechanistic relevance. Intestinal barrier function, transporters, and metabolic enzymes were assessed to exclude alternative mechanisms.
Results: ABX-c markedly disrupted microbial diversity and reshaped bile acid composition, characterized by depletion of secondary bile acids without altering total bile acid levels. This was accompanied by significantly reduced VEN Area Under the Concentration–time curve (AUC) and maximum concentration (Cmax) without changes in elimination parameters, indicating impaired absorption. Secondary bile acids positively correlated with VEN exposure. Tauroursodeoxycholic acid demonstrated superior solubilizing capacity in vitro, and in vivo reconstitution of bile acid–mediated micellar solubilization restored VEN exposure in antibiotic-treated rats. Alterations in P-gp, CYP3A11, or intestinal morphology were unlikely to explain the reduced exposure.
Conclusions: Microbiota depletion reduces VEN bioavailability by impairing bile acid–mediated micellar solubilization, identifying the microbiota–bile acid axis as a key determinant of VEN absorption and a potential clinical risk during prolonged antibiotic co-exposure.
