Cisplatin-induced hearing loss: influence of the mode of drug administration in the guinea pig

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 determi ne the influence of the mode of cisplatin administration and pharmacokineti cs on the ototoxic side-effect, the concentrations of cisplatin and the bio transformation product monoaquated cisplatin were determined in blood ultra filtrate using liquid chromatography with post-column derivatization. Ototo xic effect was evaluated as difference in pre- and 96 h post-exposure audit ory brainstem response (ABR) threshold. The cisplatin peak concentration wa s considerably higher, 19.2 +/- 2.4 mu g/ml, in the bolus injection group t han in the infusion group, 6.7+/-0.5 mu g/ml (mean+/-S.E.M.). The area unde r 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 b olus injection group, 340 +/- 5 mu g/ml/min. For monoaqua cisplatin, the AU C 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 v ariability in susceptibility to ABR threshold shift was far greater than th e variability in pharmacokinetics, suggesting that other factors are more i mportant in determining the degree of hearing loss. (C) 2000 Elsevier Scien ce B.V. All rights reserved.