Cisplatin-induced hearing loss: influence of the mode of drug administration in the guinea pig
Cisplatin-induced hearing loss: influence of the mode of drug administration in the guinea pig
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DOI：
10.1016/s0378-5955(99)00190-2
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发表时间：
2000-02-01
期刊：
影响因子：
2.8
通讯作者：
Ehrsson, H
中科院分区：
文献类型：
--
作者：
Ekborn, A;Laurell, G;Ehrsson, H
将顺铂（8 mg/kg）静脉内给予豚鼠，15 s推注（25只动物）或1 h输注（28只动物）。为探讨顺铂给药方式和药代动力学对耳毒性副作用的影响，采用柱后衍生化液相色谱法测定血超滤液中顺铂及其生物转化产物单水合顺铂的浓度。耳毒性效应以暴露前和暴露后96 h听性脑干反应（ABR）阈值的差异来评价。推注组的顺铂峰值浓度为19.2 ± 2.4 μ g/ml，显著高于输注组的6.7 ± 0.5 μ g/ml（平均值± S.E.M.）。输注组中顺铂的血液超滤液浓度时间曲线下面积（AUC）为442+/-26 μ g/ml/min，略大于推注组中的340 +/-5 μ g/ml/min。对于单水合顺铂，AUC在两组之间没有差异（推注：30.8 +/- 1.5 μ g/ml/min，输注：34.1 +/- 3.3 μ g/ml/min）。在20和12.5 kHz下，两组均观察到显著的耳毒性效应，但两组之间的阈值偏移程度无差异。ABR阈值偏移敏感性的个体间变异性远大于药代动力学的变异性，这表明其他因素在确定听力损失程度方面更重要。(C)2000爱思唯尔科技有限公司。保留所有权利。
Cisplatin (8 mg/kg) was given intravenously to guinea pigs either as a 15 s bolus injection (25 animals) or as a 1 h infusion (28 animals). To determine the influence of the mode of cisplatin administration and pharmacokinetics on the ototoxic side-effect, the concentrations of cisplatin and the biotransformation product monoaquated cisplatin were determined in blood ultrafiltrate using liquid chromatography with post-column derivatization. Ototoxic effect was evaluated as difference in pre- and 96 h post-exposure auditory brainstem response (ABR) threshold. The cisplatin peak concentration was considerably higher, 19.2 +/- 2.4 mu g/ml, in the bolus injection group than in the infusion group, 6.7+/-0.5 mu g/ml (mean+/-S.E.M.). The area under the blood ultrafiltrate concentration time curve (AUC) for cisplatin was slightly greater in the infusion group, 442+/-26 mu g/ml/min, than in the bolus injection group, 340 +/- 5 mu g/ml/min. For monoaqua cisplatin, the AUC was not different between the groups (bolus injection: 30.8 +/- 1.5 mu g/ml/min, infusion: 34.1 +/- 3.3 mu g/ml/min). A significant ototoxic effect was observed in both groups at 20 and 12.5 kHz, but there was no difference between the groups in the extent of threshold shift. The interindividual variability in susceptibility to ABR threshold shift was far greater than the variability in pharmacokinetics, suggesting that other factors are more important in determining the degree of hearing loss. (C) 2000 Elsevier Science B.V. All rights reserved.