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

Abstract

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.

Biological Monitoring of Exposure to Cisplatin in Rats Using SOS Chromotest

“…According to the pharmacokinetic study by Nagai, Hotta, and Yamamura (1995), about 35% of the dose has been excreted in the urine over 90 minutes after the CDDP injection to rats, and this has been detected mainly as unchanged CDDP. Because the electrophilic DNA-reactive form of CDDP is divalent cation Pt(NH 3 ) 3 2+ , the monitoring of unchanged CDDP is very important in pharmacokinetic study as well as in prognosis of chemotherapy.…”

Strategies for Prevention of Toxicity Caused by Platinum‐Based Chemotherapy: Review and Summary of the Annual Meeting of the Blood–Brain Barrier Disruption Program, Gleneden Beach, Oregon, March 10, 2001

“…Sodium thiosulfate binds covalently to the electrophilic platinum, rendering the platinum inactive. 17–21 Elferink et al 17 reported that sodium thiosulfate reacts irreversibly with cisplatin to form Pt(S 2 O 3 ) 4 and that sodium thiosulfate must be administered before the administration of cisplatin for neutralization. More than 100 published reports have identified a protective effect of sodium thiosulfate.…”

Impact of Superselective Transarterial Infusion Therapy of High-Dose Cisplatin on Maxillary Cancer with Orbital Invasion

“…Sodium thiosulfate, which neutralizes cisplatin, enables us to administer massive cisplatin doses directly to feeding arteries of the tumor because it mitigates systemic side effects, such as myelosuppression and renal dysfunction. [19][20][21] Fortunately, none of the patients presented with leukopenia or renal dysfunction before treatment in this study, and we could safely use cisplatin in all subjects. We observed mild leukopenia in only 1 patient who received Taxotere combined with cisplatin.…”