Strain-dependent neuronal disposition and toxicity of paclitaxel in mice

Paclitaxel is an antineoplastic agent that is associated with debilitating adverse effects, especially paclitaxel-induced peripheral neuropathy (PIPN). Although preclinical models have been used to characterize the mechanisms underlying PIPN, experimental differences in these models, including the dose, route, schedule of the drug, and the species and strain of the animals used, limit our ability to compare and interpret results. Furthermore, uncertainties persist regarding potential dependence of paclitaxel disposition and toxicity on the route of administration or genetic background of the animal model. In this study, we address this gap by systematically investigating the relationship among route- and strain-specific pharmacokinetic profiles, organ accumulation, and the associated toxicity phenotypes in preclinical models of PIPN. Using a panel of 7 commonly used mouse strains, we observed that the plasma pharmacokinetics of paclitaxel are strain dependent. Using 2 representative strains (C57Bl/6 and CD2F1), longitudinal studies show similar results for distribution of paclitaxel in the dorsal root ganglia (DRG) within the peripheral nervous system, with a 2-fold magnitude of difference. Ensuing studies indicated that the accumulation of paclitaxel in the DRG is correlated with susceptibility to mechanical allodynia, a key marker of PIPN. Our study implies that DRG accumulation, rather than plasma exposure, contributes to the development of PIPN, and this understanding is expected to inform the further development of translationally relevant models and effective therapeutic strategies for managing PIPN.

This investigation compares paclitaxel pharmacokinetics using 7 strains of mice and 2 routes of administration and longitudinally explores pharmacodynamics using 2 representative strains, which informs cross-study comparisons and the validation of translationally relevant model systems. These findings support the notion that accumulation within dorsal root ganglia, rather than plasma exposure, is correlated with the development of peripheral neuropathy. This insight is anticipated to guide the future development of effective therapeutic strategies for managing paclitaxel-induced peripheral neuropathy.