Protective effect of organic cation transport inhibitors on cis-diamminedichloroplatinum-induced nephrotoxicity

Abstract

Cis-diamminedichloroplatinum (II) (cisplatin) is a frequently used cancer chemotherapeutic agent. Nephrotoxicity is a serious dose-limiting side effect. Many approaches have been studied for protective action against cisplatin-induced nephrotoxicity, but with the exception of diuretics and hydration none are in widespread use. We have used a modified Sperber technique in unanesthetized hens to examine the effect of cisplatin on renal organic cation and anion transport and on renal morphology. The effects of the organic cation transport inhibitors quinine and cyanine on cisplatin-induced toxicity also were evaluated. Administration of cisplatin (3.0 mg/kg i.v.) produced nephrotoxic and lethal effects. Four days after cisplatin administration there was a significant inhibition of renal tubular excretory transport of the organic cation tetraethylammonium and the organic anion p-aminohippuric acid. Acute multifocal tubular necrosis of the proximal tubules was present. Administration of quinine (1.5 mumol/min) and cyanine (0.122 mumol/min) protected against the lethal effects, the inhibition of renal organic cation and anion transport and the renal lesions induced by cisplatin.