KINETICS OF GENTAMICIN UPTAKE AND RELEASE IN THE RAT - COMPARISON OF INNER-EAR TISSUES AND FLUIDS WITH OTHER ORGANS
KINETICS OF GENTAMICIN UPTAKE AND RELEASE IN THE RAT - COMPARISON OF INNER-EAR TISSUES AND FLUIDS WITH OTHER ORGANS
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DOI：
10.1172/jci112463
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发表时间：
1986-05-01
影响因子：
15.9
通讯作者：
SCHACHT, J
中科院分区：
文献类型：
--
作者：
HUY, PTB;BERNARD, P;SCHACHT, J
研究了庆大霉素在大鼠内耳液体和组织、肾皮质以及对氨基糖苷类毒性作用不敏感的器官中的进入和释放动力学。采用不同的给药模式以获得不同的药物血浆浓度模式。进行电生理学和组织学检查以关联药代动力学和耳毒性。结果表明：（a）内耳组织对药物的摄取是剂量依赖性的，并且表现出快速饱和动力学，浓度平台为约1 μ g/mg蛋白质。(b)外淋巴液和内淋巴液与血浆浓度的比值较低，这与药物在内耳中的蓄积超过血浆中药物水平的概念不符，这被认为是耳毒性的基本机制。(c)在肾皮质中，动力学似乎与内耳相似，但达到的浓度比耳蜗组织高10倍。(d)在其他器官（肝、心、肺和脾）中，在实验持续时间内未显示饱和。(e)耳毒性似乎与药物渗透到隔室有关，其中消失的半衰期极其缓慢。(f)组织对药物的快速吸收、早期饱和和长期暴露可能是内耳和肾脏毒性发展的原因。
The kinetics of entry and release of gentamicin was investigated in fluids and tissues of the inner ear of the rat, as well as in renal cortex, and in organs that do not share susceptibility to the toxic effects of aminoglycosides. Various modes of administration were used to achieve different patterns of drug plasma cncentrations. Electrophysiological and histological examinations were performed to correlate pharmacokinetics and ototoxicity. Results show that: (a) the uptake of the drug by the inner ear tissues is dose dependent and manaifests a rapid saturation kinetics with a concentration plateau of about 1 .mu.g/mg of protein. (b) The low ratio of the perilymph and endolymph to plasma concentrations argues against the concept of an accumulation of the drug in the inner ear over drug levels in plasma, which has been considered as the basic mechanism of ototoxicity. (c) In renal cortex, the kinetics appears similar to that of the inner ear but the concentrations achieved are 10-fold higher than in cochlear tissues. (d) In other organs (liver, heart, lung, and spleen), no saturation could be demonstrated within the duration of the experiment. (e) Ototoxicity seems to be related to the penetration of the drug into compartment(s) from which the half-life of disappearance is extremely slow. (f) Rapid uptake, early saturation, and long exposure of the tissues to the drug may account for the development of toxicity in inner ear and kidney.