I. Cisplatin (cDDP) transport and accumulation in isolated segments of the rabbit renal proximal tubule. II. The effects of administering a continuous infusion of organic ions to cDDP treated rats.

摘要

Cisplatin (cDDP) is a chemotherapeutic agent used to treat various tumor types, but is limited in its efficacy by renal toxicity. Therefore, this project was designed to examine renal handling mechanisms for cDDP at the tissue level and ways to safeguard the kidney from cDDP induced renal insufficiency in the whole organism. At the tissue level, examination of transport and cellular accumulation process for cDDP, in each of the renal proximal tubular segments, S₁, S₂, and S₃, was recorded using the isolated perfused tubule technique. At the organism level, cimetidine, para-aminohippuric acid (PAH), and arginine, were continuously administered via osmotic pumps to rats receiving cisplatin treatment. General conclusions from the former study indicate that NAC-cDDP is transported and accumulated more avidly than cDDP at the basolateral membrane. NAC-cDDP induced acute severe toxicity, while cDDP did not. The addition of the organic anion PAH to the basolateral membrane inhibited transepithelial flux and accumulation of cDDP-NAC and subsequently abrogated toxicity. When the organic cation tetraethylammonium (TEA) was applied to the basolateral membrane, the transepithelial flux and cellular accumulation of cDDP was significantly reduced. Thus, it appears NAC-cDDP is transported by the organic anion transport system and cDDP is transported by the organic cation transport system. Secondly, cDDP and NAC-cDDP are both transported across the luminal membrane at similar rates but cellular accumulation is significantly greater for NAC-cDDP. NAC-cDDP induced severe toxicity at the luminal membrane but coperfusion with arginine significantly lowered cellular accumulation of NAC-cDDP and prevented toxicity. The application of TEA to the luminal membrane significantly decreased cDDP accumulation, implying that cDDP uses the organic cation transporter. The last experiment tested these particular effects in the whole organism. The data for this study indicates cDDP induces nephrotoxicity at a dose of 6 mg/kg, while a continuous infusion of the organic ions cimetidine, PAH, and arginine improves renal function significantly in cDDP treated rats.