Seasonal Modulation of the 8‐and 24‐Hour Rhythms of Ondansetron Tolerance in Mice

Abstract

Ondansetron (Zophren®) is a serotonin 5HT₃-receptor antagonist used primarily to control nausea and vomiting caused by cytotoxic chemo‐and radio‐therapy. Tolerance to this drug shows both 24 and 8 h periodicities. In this framework, this study aimed to determine whether these ondansetron tolerance rhythms are modulated by season. The chronotoxic effect of a fixed dose (3.5 mg/kg, i.p.) of the drug was investigated with reference to both time of the day and year dependencies. Season‐related studies were performed on 560 male Swiss mice, 10 to 12 wks old, synchronized with L:D=12:12 for three weeks. During a 1 yr span (2005), four 24 h studies were performed with a single dosing time at 1, 7, 13, and 19 hours after light onset (HALO), respectively. Tolerance was assessed daily during a 40‐day span after acute ondansetron treatment. Both χ² test and cosinor methods were used to analyze the time series data. Statistically significant dosing time‐dependent changes were validated in both yearly and daily time scales. The 24 h mean survival rate peaked in spring (92%) compared to fall (72%), the 20% difference being statistically significant (χ² test with p<0.05 and cosinor with p<0.0001 for seasonal rhythm detection and with a peak time, Ø,=April 3±6.6 days). A 24 h rhythm was also detected in each of the seasonal time points. However, the curve pattern was monophasic in fall as well as spring. In fall, a large amplitude (A) circadian rhythm was detected that peaked at 19 HALO, while in the spring, a small circadian rhythm was detected that peaked at 1 HALO. The curve pattern was biphasic in summer (with large A) and in winter (with a small A). The existence of two peaks of equal magnitude in winter (100% survival rate) and in summer (100% and 90%) suggests the presence of both circadian and ultradian rhythms rather than an ultradian component of the 24 h period. The seasonal modulation of ondansetron circadian chronotolerance seems to involve several rhythm parameters: season‐related changes in the 24 h mean (M), amplitude (A), acrophase location (Ø), as well as bimodal curve patterns including the coexistence of rhythms with respectively 24 and 8 h periods in winter and summer. In conclusion, tolerance to ondansetron varies not only according to the 24 and 8 h periods but also according to seasons, which suggests the complexity of ondansetron toxicity rhythms. Seasonal modulation of ondansetron tolerance may also influence the strategies of chemo‐and chrono‐therapy, and it is therefore necessary to take it into account in clinical drug‐delivery protocols to minimize side effects of cytotoxic anticancer and antiemetic agents.

• Ondansetron
• Tolerance
• Mice
• Circadian
• Serotonin antagonist

Notes

The first two authors contributed equally to this work.