治疗剂量阿米卡星在新生豚鼠药代动力学及耳毒性研究

Experimental study on the pharmacokinetics and ototoxicity of amikacin with therapeutic doses in neonatal guinea pig

目的 :明确新生豚鼠对氨基糖甙类抗生素耳毒性有无更高敏感性。方法 :以扫描电镜及光镜观察人类等效治疗剂量下阿米卡星 (AMK)对 36只新生及成年豚鼠耳蜗毛细胞的影响 ,并用TDx检测新生及成年组豚鼠血浆AMK药代动力学。结果 :( 1)药代动力学 :新生及成年豚鼠组均为二室开放性模型 ,峰浓度及达蜂时间无显著性差异 ,但新生组豚鼠清除率较成年组明显降低 (分别为 0 .0 0 4 4± 0 .0 0 11和 0 .0 0 88± 0 .0 0 14L/min .kg ,P <0 .0 1) ,消除半衰期明显延长 (分别为 70 .89± 13.38和4 3.2 4± 8.0 3min ,P <0 .0 1) ,曲线下面积明显增大 (分别为 114 6 1.5± 4 317.2和 816 5 .9± 32 12 .5 ,P <0 .0 1)。 ( 2 )耳蜗毛细胞形态学 :新生组豚鼠损伤出现早且严重 ;停药后毛细胞缺失数继续增多。结论 :AMK对新生、成年豚鼠耳蜗均有不同程度损害 ,并随用药时间延长而加重。新生豚鼠的敏感性高可能与该药从体内排出慢。

Objective:To clarify the possibility of higher sensitivity to ototoxicity of aminoglycosides in neonatal animal.Methods:The difference in ototoxicity was studied by scanning electron-microscopy and microscopy between neonatal and adult groups of 36 guinea pigs administrated with therapeutic doses of amikacin.Pharmacokinetics was investigated in 10 guinea pigs in each group by TDx system.Results:(1)The pharmacokinetics were compatible with the model of two compartment in all age groups.There was no significant difference in the peak level and peak time.Compared with adult group, the plasma clearance was lower(0.0044±0.0011 and 0.0088±0.0014 L/min. kg, P <0.01),the half-life for elimination longer in neonatal group(70.89±13.38和43.24±8.03min, P <0.01),and AUC was larger(11461.5±4317.2和8165.9±3212.5, P <0.01).(2)On histological study for cochlea,the damage was more severe in neonatal groups than that in adults.The severity of cochlea damage was getting worse with a prolonged course of the administration.Continuous damage was observed after the drug had been stopped.Conclusion:The study shows that there is significant ototoxicity of AMK to cochlea in neonatal guinea pigs even with therapeutic doses equal to that in clinical use.The higher sensitivity to ototoxicity of AMK in neonatal animal is related to their much slow clearance and high possibility of accumulation for AMK.