Dosing Time-Dependent Effects of Paclitaxel on Peripheral Neuropathy in Mice

Paclitaxel (PTX) is a widely used anticancer drug that frequently causes peripheral neuropathy, particularly mechanical allodynia, which is the sensation of pain from mechanical stimuli that are not normally painful, as an adverse effect. In this study, we investigated the effectiveness of chronotherapy on PTX-induced mechanical allodynia in mice. Male C57BL/6J mice were intravenously administered PTX at 1:00, 5:00, 9:00, 13:00, 17:00 or 21:00 of the day, and mechanical allodynia was assessed using the Von Frey test. Significant circadian variations were observed at the 50% withdrawal threshold, with the lowest values observed in the PTX 9:00 group. When PTX was administered at 9:00 or 21:00, the 50% withdrawal threshold of the PTX 9:00 group was significantly lower than that of the control group. In contrast, the PTX 21:00 group recovered from mechanical allodynia earlier. Repeated administration of PTX showed that the PTX 21:00 group recovered from mechanical allodynia earlier than the PTX 9:00 group. The plasma concentrations of PTX 12 h after administration were significantly higher in the PTX 9:00 group than in the PTX 21:00 group, suggesting the involvement of circadian variations in drug metabolism. No significant differences were found in body weight changes or ALT levels among the control, PTX 9:00, and PTX 21:00 groups. Chronotherapy can ameliorate PTX-induced mechanical allodynia in mice, potentially contributing to improved cancer treatment in humans. Further studies on the pharmacokinetics and antitumor effects of PTX are required to understand the implications of chronotherapy fully.