Mistry P, Lee C, McBrien D C
Department of Biology and Biochemistry, Brunel University, Uxbridge, Middlesex, UK.
Cancer Chemother Pharmacol. 1989;24(2):73-9. doi: 10.1007/BF00263124.
The appearance of low-molecular-weight metabolites of cisplatin in the cytosol of cells from the cortex and outer medulla of the rat kidney has been examined using HPLC up to 24 h following cisplatin administration. Comparison was made between these metabolites and those present in plasma, urine and liver. The effect of sodium chloride (NaCl) pretreatment, which is known to reduce cisplatin-induced nephrotoxicity, on these metabolites was also investigated. Platinum levels in the kidney cortex and medulla and the cytosol reached maximal levels within 1 h of i.p. injection of 5 mg/kg cisplatin. At least six platinum species, including cisplatin, were present 1 h post-dosing, with the principal species being the parent drug; all of these species were either neutral or negatively charged. Although the concentration of most of the platinum species fell with time, that of one species eluting before cisplatin rose, and by 24 h it was the major metabolite. Cisplatin and two other major cytosolic platinum species were also present in urine and plasma, both of which also contained a number of charged species that were absent from the cytosol. The liver cytosol contained at least five metabolites 1 h post-dosing, but, in contrast to the kidney cytosol at the same time, the predominant species was that eluting before cisplatin and not cisplatin itself. One of the metabolites in the cytosol and urine had the same retention time as an adduct of cisplatin with glutathione and with cysteine. Urinary samples also contained a metabolite coeluting with aquated cisplatin. Pretreatment of animals with NaCl significantly reduced the platinum concentration in the kidney, with a corresponding decrease in the cytosolic metabolites; this may have contributed significantly to the reduction in cisplatin-induced nephrotoxicity after NaCl pretreatment. NaCl also significantly reduced a possible aquated species present in the urine, which may also have contributed to the reduction in nephrotoxicity. The data suggest that cisplatin itself may be the nephrotoxic species, since it is the intracellular platinum compound present in highest concentration during the early critical period after its administration.
在大鼠肾脏皮质和外髓质细胞的胞质溶胶中，使用高效液相色谱法（HPLC）检测了顺铂给药后长达24小时的低分子量代谢产物的出现情况。对这些代谢产物与血浆、尿液和肝脏中的代谢产物进行了比较。还研究了已知可降低顺铂诱导的肾毒性的氯化钠（NaCl）预处理对这些代谢产物的影响。腹腔注射5mg/kg顺铂后1小时内，肾脏皮质、髓质和胞质溶胶中的铂水平达到最高水平。给药后1小时至少存在六种铂物种，包括顺铂，主要物种为母体药物；所有这些物种均为中性或带负电荷。尽管大多数铂物种的浓度随时间下降，但在顺铂之前洗脱的一种物种的浓度上升，到24小时时它是主要代谢产物。尿液和血浆中也存在顺铂和其他两种主要的胞质溶胶铂物种，两者还含有一些胞质溶胶中不存在的带电物种。给药后1小时，肝脏胞质溶胶中至少含有五种代谢产物，但与同时期的肾脏胞质溶胶相反，主要物种是在顺铂之前洗脱的物种，而不是顺铂本身。胞质溶胶和尿液中的一种代谢产物与顺铂与谷胱甘肽和半胱氨酸的加合物具有相同的保留时间。尿液样本中还含有与水合顺铂共洗脱的代谢产物。用NaCl预处理动物可显著降低肾脏中的铂浓度，同时胞质溶胶代谢产物相应减少；这可能对NaCl预处理后顺铂诱导的肾毒性降低有显著贡献。NaCl还显著降低了尿液中可能存在的一种水合物种，这也可能有助于降低肾毒性。数据表明，顺铂本身可能是肾毒性物种，因为它是给药后早期关键时期细胞内浓度最高的铂化合物。
