D-Methionine and cisplatin ototoxicity in the guinea pig: D-methionine influences cisplatin pharmacokinetics.
D-Methionine has recently been advocated as a protectant against cisplatin toxicity. The use of systemic D-methionine as a protector was studied in 58 guinea pigs. Kinetics and distribution of [11CH(3)]D-methionine was analysed by positron emission tomography. Cisplatin and the monohydrated complex of cisplatin was quantified in blood ultrafiltrate using reversed-phase liquid chromatography with post-column derivatisation. Administration of 300 mg/kg of D-methionine caused a 30% decrease in the area under the concentration-time curve (AUC) of cisplatin. The toxic effect of cisplatin was studied after dose adjustment of cisplatin, i.e. with similar cisplatin AUC in the group receiving D-methionine and the saline control group. A significant ototoxic effect, measured as difference in pre- and 96 h post-treatment electrophysiological hearing threshold (auditory brainstem response), was observed at stimulus frequencies of 30 and 20 kHz. There was no difference between the groups in the extent of threshold shift. Quantitative outer hair cell counts showed a similar loss of cells in the two groups. All animals had a significant increase in plasma-creatinine but there was no difference between the groups. The results indicate that protection from cisplatin ototoxicity by systemic D-methionine can be explained by a lowered systemic exposure to the drug.
Ekborn
Andreas
A
Department of Otorhinolaryngology, Head and Neck Surgery, Karolinska Hospital, SE-171 76, Stockholm, Sweden. andreas.ekborn@ks.se
Laurell
Göran
G
Johnström
Peter
P
Wallin
Inger
I
Eksborg
Staffan
S
Ehrsson
Hans
H
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000506:poisoning*; D001835:Body Weight / Q000187:drug effects; D002945:Cisplatin / Q000493:pharmacokinetics / Q000506:poisoning*; D003401:Creatine / Q000378:metabolism; D019610:Cytoprotection; D004423:Ear; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000494:pharmacology*; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D000970:Antineoplastic Agents; D008715:Methionine; D003401:Creatine; D002945:Cisplatin