CIRCADIAN VARIATION IN AMIKACIN CLEARANCE AND ITS EFFECTS ON EFFICACYAND TOXICITY IN MICE WITH AND WITHOUT IMMUNOSUPPRESSION

A once-daily dosage regimen has been recently recommended in the use o f aminoglycoside antibiotics since they induce a postantibiotic effect . In choosing this regimen, one must determine the most appropriate ti me of day for administration of the drug. We investigated the effects of the timing of amikacin (AMK) administration on the kinetics, the ef ficacy against intraperitoneal infection with Pseudomonas aeruginosa, and the toxicity of AMK in mice with and without immunosuppression. We found circadian variations in the kinetics, efficacy, and toxicity of the drug in mice. Male and female ICR mice, which were housed under a light-dark (12:12 h) cycle with free food and water intake, were inje cted subcutaneously with AMK sulfate 50 mg/kg body wt. There was a cir cadian variation in AMK clearance for both sexes with the maximum valu e in the dark phase and the minimum in the light phase after a single administration. When AMK 500 mg/kg/day was repeatedly administered onc e daily for 30 days, higher toxicity was demonstrated in mice injected with the drug at the time of day with lower AMK clearance, although n o difference was demonstrated in the toxicity between the two time poi nts with different AMK clearance when AMK 1,500 mg/kg was administered in a single dose. The ED50 of AMK to cure the infected mice in the mi dlight phase (13:00 h) with lower clearance was significantly lower th an that in the middark phase (01:00 h) with higher clearance. In contr ast, the ED50 in the early light phase (09:00 h) was significantly low er than that in the early dark phase (21:00 h), although AMK clearance was not different between these two different time points. In mice pr emedicated with cyclophosphamide to suppress immune functions, the dif ference in the ED50 of AMK was still demonstrated between 13:00 and 01 :00 h, but not between 09:00 and 21:00 h. The present study shows not only that there were circadian variations in both AMK clearance and to xicity after repeated administration, but also that there was a circad ian variation in the efficacy of AMK in mice infected with P. aerugino sa. These results suggest that the timing of drug administration shoul d be considered in pharmacotherapy with AMK and that the most appropri ate time of administration in mice and nocturnal animals may be in the midlight (resting) phase. They also suggest that the ED50 of AMK agai nst P. aeruginosa infection may be influenced not only by the circadia n variation in pharmacokinetics but also by the variations in immune s ystems suppressed by cyclophosphamide.