アミノ配糖体薬剤の体内動態と聴器障害

Abstract

We investigated the relationship between kanamycin ototoxicity and its serum and perilymph levels when administered to rabbits by rapid i. v. or continuous i. v. infusion.The peak serum level after rapid i. v. was 110-fold higher than that after 24-h infusion, while the peak perilymph level after rapid i. v. was 2.5-fold higher than that after 24-h infusion. Trough serum and perilymph levels 24-h after the start of administration were significantly higher after the 24-h infusion than those after the other administration methods. There was no significant difference in the area under the curve (AUC) of serum level between rapid i. v. and 1-h infusion, while the AUCs of 12-h infusion and 24-h infusion were significantly smaller compared to those of the former two. Also, the slower the administration speed, the smaller the AUC of the perilymph level was. In the 30-day consecutive dosing, rapid i. v. tended to show some slight ototoxicity compared to 12-h infusion. There was a relationship between the peak renal level and the serum concentration, while the trough level became significantly higher as the rate of infusion decreased. Changes indicating renal toxicity were not seen after 30-day consecutive dosing at any rate of administration, expcept for slight changes in BUN and creatinine, and a significant in- crease in kidney weight for the 12-h infusion. No histopathological abnormality was detected in any of the animals. The results of the present study demonstrated that the increased trough serum level due to maintenance of the serum level over a prolonged period in continuous infusion or divided intermittent dosing causes ototoxicity. It was, therefore, suggested that kanamycin administered once a day or by rapid i. v. is less toxic than when given by divided intermittent dosing or continuous infusion.