INFLUENCE OF FEEDING SCHEDULE ON CHRONOPHARMACOLOGICAL ASPECTS OF GENTAMICIN IN MICE

The effects of the time of day of drug administration on the subchroni c toxicity and pharmacokinetics of gentamicin, as well as the role of feeding schedule on circadian rhythms, were investigated in mice. ICR male mice were housed in a light-dark (LD) cycle (12:12) with food and water ad libitum (ALF) or under a time-restricted feeding (TRF) sched ule (feeding time: 8 h during the light phase) for 1 day or 14 days be fore drug administration. The animals were given a single subcutaneous dose of gentamicin 180 mg/kg for the kinetic studies and subcutaneous doses of gentamicin 180 mg/kg/day for 14 days or 220 mg/kg/day for 18 days for the subchronic toxicity studies. A significant dosing-time d ependency was shown for mortality and body weight loss, with higher va lues at midlight and lower ones at the middark (p < 0.05). A significa nt circadian rhythm was also found for gentamicin kinetics in ALF mice , with the highest clearance at middark and the lowest one at midlight (p < 0.01). The kinetic rhythm of gentamicin coincided well with the toxicity rhythm of the drug. The TRF schedule had a marked influence o n the rhythms of gentamicin kinetics and toxicity, showing lowest clea rance and higher toxicity at middark. The rhythm of subchronic toxicit y of gentamicin seems to be due, at least in part, to the rhythm in ki netics and is strongly influenced by the feeding schedule. Thus, the t iming of dosing is an important factor in the kinetics and the subchro nic toxicity of gentamicin administration in mice, and the manipulatio n of feeding schedule can modify the rhythm of the toxicity by changin g the rhythm of gentamicin kinetics.