Influence of Consecutive Nab-Paclitaxel Chemotherapy Cycles on Gut Microbiota and Pharmacokinetic Behavior

IntroductionNab-paclitaxel is a mainstay of treatment for a broad spectrum of cancers and is typically administered over multiple cycles. The anti-mitotic effects of nab-paclitaxel are well-established. However, the systemic impact of consecutive treatment cycles on host physiology remains largely unexplored. Of particular interest is the gut microbiota and its regulatory role in drug metabolism. This study aimed to investigate the effects of consecutive nab-paclitaxel chemotherapy cycles on gut microbiota composition, intestinal barrier function, and pharmacokinetic (PK) behavior in rats.MethodsTwenty-four Sprague-Dawley rats were randomly assigned to one-, two-, or three-cycle chemotherapy groups and received nab-paclitaxel via tail vein injection. Plasma drug concentrations were measured by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS), gut microbial composition was analyzed using 16S Ribosomal RNA (16S rRNA) sequencing, and hepatic CYP3A and CYP2C expression was assessed by Western blot and Quantitative Polymerase Chain Reaction (qPCR).ResultsConsecutive nab-paclitaxel administration significantly altered the gut microbiota, decreasing Actinobacteriota and Firmicutes while increasing Proteobacteria and Cyanobacteria in a cycle-dependent manner. Microbial diversity indices, including Observed species and Rao's quadratic entropy, increased after multiple cycles. Pharmacokinetic analysis showed that clearance, mean residence time, and volume of distribution decreased, whereas Area Under the Curve (AUC) and Maximum Plasma Concentration (Cmax) increased significantly after repeated dosing. However, no significant differences were observed in CYP3A1 or CYP2C11 protein or Messenger RNA (mRNA) expression, suggesting that nab-paclitaxel may influence pharmacokinetics through non-CYP-dependent pathways potentially mediated by gut microbiota-host interactions.ConclusionIn conclusion, consecutive nab-paclitaxel chemotherapy cycles induce gut microbiota dysbiosis and alter pharmacokinetic profiles via non-CYP-dependent mechanisms, highlighting the critical role of the microbiota-gut-liver axis in chemotherapeutic drug disposition and providing a theoretical basis for microbiota-targeted interventions to optimize chemotherapy efficacy.