Influence of hydration on ultrafilterable platinum kinetics and kidney function in patients treated withcis-diamminedichloroplatinum(II)

Abstract

It has been reported that hypertonic saline provides protection against the renal toxicity of cisplatin (CDDP). We therefore evaluated its influence on the plasma and urinary pharmacokinetics of ultrafilterable platinum and kidney function as estimated by creatinine, inulin and PAH clearance. We undertook a randomized trial including two groups of ten patients receiving 100 mg/m2 CDDP in isotonic (group 1) or hypertonic saline (group 2) by a 20-min infusion. The hydration consisted of dextrose in group 1 and isotonic saline in group 2. Maximal concentration (Cmax), protein binding and cumulative urinary excretion were significantly higher in the dextrose group. Urinary flow decreased in this group but not in the other one. Inulin clearance was higher in the dextrose group than in the saline group and P-aminohippuric acid (PAH) clearance was not significantly different in these groups of patients. Hyponatremia was observed in the dextrose group. These results suggest that hypertonic saline infusion and saline hydration may enhance the diffusion of CDDP into tissues, lowering Cmax and renal excretion of platinum. The reduction of protein binding may indicate a diminution of aquation of CDDP in plasma. Our results suggest that the infusion of CDDP in hypertonic saline with salt hydration could exert a protective effect on the kidney. Moreover, there is a lessening of the risk of cellular hyperhydration. However, the better influence of dextrose hydration on glomerular filtration leads us to recommend a combination of the two methods of hydration for better tolerance and efficacy.

Stress response inhibits the nephrotoxicity of cisplatin

“…It has been proposed that volume repletion of patients with isotonic saline protects against cisplatin-induced nephrotoxicity by flushing the cisplatin out of the body, limiting uptake into the proximal tubule cells (9). Patients treated with cisplatin are generally given up to 6 l saline/day iv (28,34).…”

“…Several theories have been proposed to explain the protective effect of hydration against cisplatin nephrotoxicity. Some investigators have suggested that hypertonic saline and saline hydration protect the kidney by increasing the rate of cisplatin excretion (9). Others have proposed that the salt provides a high concentration of chloride ions, which prevents the dissociation of the chloride ions from the platinum molecule, thereby reducing the formation of the reactive, aquated species of cisplatin (5,10).…”

Cisplatin-induced nephrotoxicity and targets of nephroprotection: an update

“…Patients treated with high doses of cisplatin should receive normal saline infusion (100 ml/h) prior to, during and several days following the administration of cisplatin; however, despite these measures, renal failure still occurs (Losonczy et al 2010). It has been reported that the infusion of cisplatin diluted in hypertonic saline (3%) might provide protection against the renal toxicity (Dumas et al 1990), but some studies have shown that GFR remains reduced despite this measure (Launay-Vacher et al 2008). Moreover, there is also the concern that the elevated concentration of chloride ions would prevent the formation of the aquated species responsible for the antitumor activity of cisplatin (Hanigan et al 2005).…”

Effect of Bile Acids on Hepatobiliary Transport of Cisplatin by Perfused Rat Liver

“…Thus, for a given dose, toxicity is dependent on the uptake and excretion kinetics of the drug. In this sense, several attempts have been made to improve the elimination of cisplatin in both urine (Dumas et al 1990) and bile (Basinger et al 1989), without affecting its antitumour action.…”