Reduction of cisplatin nephrotoxicity by sodium selenite:lack of interaction at the pharmacokinetic level of both compounds

Administration of sodium selenite (Na2SeO3) 1 hr before cis- diamminedichloroplatinum(II) (referred to herein as cisplatin) can protect against the nephrotoxicity of cisplatin. The pharmacokinetic aspects of this interaction were studied in rodents with radiolabeled selenite and cisplatin. Total [75Se]selenium in plasma consisted of [75Se]selenium in plasma proteins and [75Se]selenite in plasma ultrafiltrate. After a short distribution phase, the elimination of [75Se]selenite and total [75Se]selenium proceeded biphasically in the rat, with an initial plasma elimination half-life of [75Se]selenite of 22 ± 2 min. Coadministration of cisplatin had no effect on the initial nor on the much slower terminal elimination phase of [75Se]selenite nor of total [75Se]selenium. Sodium selenite, in doses protecting against the nephrotoxicity of cisplatin, did not significantly affect areas under the plasma concentration time curve from 0-6 hr nor the initial plasma half-lives of [195mPt]cisplatin (t( 1/2 ), 28 ± 2 min) and total [195mPt]platinum (t( 1/2 ), 30 ± 3 min) in plasma. The much slower terminal elimination phases in plasma and the cumulative urinary excretion of [195mPt]cisplatin and total [195mPt]platinum were neither influenced by sodium selenite. Sodium selenite does not react chemically with cisplatin in vitro. Apparently, bioactivation of selenite is required for its protective effect in vivo. Distribution studies in a mice tumor model indicated that [75Se]selenium is concentrated strongly in the kidney and that the bioactivation of selenite also most likely occurs primarily in the kidneys. We conclude that sodium selenite protects rodents against cisplatin-induced nephrotoxicity without influencing the systemic availability of cisplatin and total platinum. Further studies are necessary to establish the clinical value of sodium selenite as chemoprotector against cisplatin-induced nephrotoxicity.