Ototoxicity, nephrotoxicity and pharmacokinetics of cisplatin and its monohydrated complex in the guinea pig.
OBJECTIVE
To evaluate and compare the ototoxicity and nephrotoxicity of cisplatin and cis-diammineaquachloroplatinum(II) ion (monohydrated complex of cisplatin, MHC, formed in vivo by hydrolysis of cisplatin) after their separate administration to guinea pigs.


METHODS
A dose of 4 mg/kg body weight of MHC was deemed suitable for the toxicity evaluation after dose titration. Electrophysiological hearing thresholds (auditory brainstem response, ABR), plasma creatinine and weight were measured in three groups of animals before and after receiving MHC 4 mg/kg (0.0141 mmol/kg), cisplatin 4.24 mg/kg (0.0141 mmol/kg, i.e. equimolar dose) or cisplatin 8 mg/kg (0.0267 mmol/kg) as an i.v. bolus injection. Cisplatin and MHC were analysed using liquid chromatography with post-column derivatization.


RESULTS
Administration of MHC 4 mg/kg caused a moderate ABR threshold shift, a significant increase in creatinine and a significant weight loss, changes similar to those seen after administration of cisplatin 8 mg/kg. Animals given cisplatin 4.24 mg/kg had a slight increase in creatinine, but had no ABR threshold shift and gained weight during the experiment. The pharmacokinetic parameters of cisplatin and MHC were estimated after administration of cisplatin 4.24 mg/kg and MHC 4 mg/kg. The area under the blood-ultrafiltrate concentration versus time curve (AUC) for cisplatin after administration of MHC 4 mg/kg was 23% (56+/-5.0 micro g.min.ml(-1)) (means+/-SD) of that after administration of cisplatin 4.24 mg/kg (240+/-25 micro g.min.ml(-1)). The AUC for MHC after administration of cisplatin 4.24 mg/kg was 20% (30+/-4.9 micro g.min.ml(-1)) of that after administration of MHC 4 mg/kg (149+/-26 micro g.min.ml(-1)).


CONCLUSIONS
MHC 4 mg/kg causes ototoxicity, nephrotoxicity and weight loss when administered to guinea pigs. The toxic effects were similar to those seen after administration of cisplatin 8 mg/kg and higher than those seen after administration of cisplatin 4.24 mg/kg.
Ekborn
Andreas
A
Department of Otorhinolaryngology, Head and Neck surgery, Karolinska Hospital, SE-171 76 Stockholm, Sweden. andreas.ekborn@ks.se
Lindberg
Annika
A
Laurell
Göran
G
Wallin
Inger
I
Eksborg
Staffan
S
Ehrsson
Hans
H
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D003404:Creatinine / Q000097:blood; D007758:Ear, Inner / Q000187:drug effects*; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects*; D005260:Female; D006168:Guinea Pigs; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male
D000970:Antineoplastic Agents; D003404:Creatinine; D002945:Cisplatin