Effects of sodium thiosulfate on the pharmacokinetics of unchanged cisplatin and on the distribution of platinum species in rat kidney: protective mechanism against cisplatin nephrotoxicity.
To investigate the mechanism underlying the protective effect against cisplatin (CDDP) nephrotoxicity of its antidote, sodium thiosulfate (STS), the effects of STS on the pharmacokinetics of unchanged CDDP and on the distribution of unchanged CDDP and high and low molecular mass metabolites (fixed and mobile metabolites) in the kidney 1 min after a bolus injection of CDDP (5 mg/kg) to rats were studied. A decrease in the plasma concentration of unchanged CDDP and an increase in the plasma concentration of mobile metabolites were observed in the rats after the bolus injection of CDDP in combination with STS infusion for 30 min (1200 mg/kg). Although STS accelerated platinum excretion during the first 10 min after CDDP injection, unchanged CDDP was not excreted in the urine in the STS-treated rats. Total kidney platinum 1 min after the bolus injection of CDDP was detected mainly as unchanged CDDP (86% of the total platinum) in the rats given CDDP alone. However, in the STS-treated rats, the total kidney platinum was decreased to 62% of the level in the rats given CDDP alone, and the platinum species detected in the kidney were mainly mobile metabolites. Only 24% of the total kidney platinum was detected as unchanged CDDP in the STS-treated rats. The loss of body weight and increases in BUN and serum creatinine levels usually observed after a bolus injection of CDDP were completely prevented by STS coadministration. The present study provides information about unchanged CDDP pharmacokinetics and the distribution of unchanged CDDP and some of its generic metabolites in the kidney when STS is coadministered as an antidote. These results show that the protective effect of STS against CDDP nephrotoxicity can be attributed to the formation of inactive mobile metabolites by a direct reaction between unchanged CDDP and STS in the systemic circulation, resulting in a reduction in the amount of unchanged CDDP in the kidney.
Nagai
N
N
Department of Biopharmaceutics, Meiji College of Pharmacy, Tokyo, Japan.
Hotta
K
K
Yamamura
H
H
Ogata
H
H
D000704:Analysis of Variance; D000818:Animals; D002945:Cisplatin / Q000009:adverse effects* / Q000493:pharmacokinetics*; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013885:Thiosulfates / Q000494:pharmacology*; D014018:Tissue Distribution
D013885:Thiosulfates; C017717:sodium thiosulfate; D002945:Cisplatin