Similar pharmacokinetics and differential ototoxicity after administration with cisplatin and transplatin in guinea pigs.
Transplatin is a transisomer of cisplatin. Although cisplatin exhibits strong ototoxicity, there is no report concerning the ototoxicity of transplatin. To evaluate differences in pharmacokinetics and ototoxicity, cisplatin (7.5 mg/kg) and transplatin (30 mg/kg) were administered to guinea pigs twice at an interval of 5 days. The N1 threshold of the compound action potential was significantly elevated after administration of cisplatin. Cochleogram of the cisplatin-treated group showed severe losses of outer hair cells essentially at the basal and second turns. Transplatin, however, did not induce any detectable functional or morphological changes. Furthermore, blood urea nitrogen and creatinine levels in serum were not elevated after administration of transplatin, whereas cisplatin showed strong nephrotoxicity. The serum and perilymphatic concentrations of platinum up to 24 h after administering an equimolar dose of cis- or transplatin (7.5 mg/kg) were almost similar. As has been reported by many investigators, transplatin has no anti-tumor activity because stereochemical limitations preclude transplatin from forming intra- and interstrand closs-links with nuclear or mitochondrial DNA. From these results, it was concluded that the stereochemical structure of the platinum compound and steric interaction with target molecules such as mitochondrial DNA in the cochlear outer hair cells might be important to the ototoxic mechanism of platinum compounds.
Saito
T
T
Department of Otolaryngology, Fukui Medical School, Japan.
Zhang
Z J
ZJ
Yamada
T
T
Yamamoto
T
T
Shibamori
Y
Y
Saito
H
H
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity*; D001300:Audiometry, Evoked Response; D001309:Auditory Threshold / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002945:Cisplatin / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000633:toxicity*; D003051:Cochlea / Q000187:drug effects* / Q000378:metabolism*; D003404:Creatinine / Q000097:blood; D004272:DNA, Mitochondrial / Q000187:drug effects; D006168:Guinea Pigs; D018072:Hair Cells, Auditory, Outer / Q000187:drug effects; D006311:Hearing Disorders / Q000139:chemically induced*
D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; C034697:transplatin; D003404:Creatinine; D002945:Cisplatin