Nagai N, Kinoshita M, Ogata H, Tsujino D, Wada Y, Someya K, Ohno T, Masuhara K, Tanaka Y, Kato K, Nagai H, Yokoyama A, Kurita Y
Department of Biopharmaceutics, Meiji College of Pharmacy, Tanashi-shi, Tokyo, Japan.
Cancer Chemother Pharmacol. 1996;39(1-2):131-7. doi: 10.1007/s002800050548.
The relationships between pharmacokinetic parameters of unchanged cisplatin (CDDP) and several markers for nephrotoxicity after CDDP infusion (80 mg/m2) over 2 and 4 h were quantitated in patients with various cancers (lung, stomach and colon cancers and mediastinal tumor).
Plasma and urinary levels of unchanged CDDP were measured using a specific high-performance liquid chromatography method. Pharmacokinetic parameters were calculated according to the model-independent method. The nephrotoxicity markers, blood urea nitrogen (BUN), serum creatinine (SCr), plasma and urinary beta2-microglobulin (BMGp and BMGu), urinary N-acetyl-beta-D-glucosaminidase (NAG) and creatinine clearance (CCR) were monitored for 30 days following CDDP administration.
The maximum plasma concentration (Cmax), maximum urinary excretion rate (dAe/dt(max)), area under the plasma concentration-time curve from time zero to infinity (AUC), cumulative amount excreted in urine from time zero to infinity (Ae), total clearance (Clt), renal clearance (Clr) and plasma half-life (t1/2) of unchanged CDDP were not significantly different between the 2-h and 4-h infusion schedules. The values of the nephrotoxicity markers changed significantly following CDDP administration, suggesting that CDDP chemotherapy (80 mg/m2) caused nephrotoxicity. The Cmax of unchanged CDDP was the most informative pharmacokinetic parameter for nephrotoxicity. Cmax was related to maximum BUN, maximum SCr and minimum CCR levels in 27 CDDP treatments according to an exponential model.
In order to attain more effective CDDP chemotherapy with minimum nephrotoxicity, the present pharmacokinetic and pharmacodynamic studies suggest that the Cmax or steady-state plasma level of unchanged CDDP should be maintained between 1.5 and 2 microg/ml in a standard continuous infusion schedule over 2 h and 4 h.
对各类癌症（肺癌、胃癌、结肠癌及纵隔肿瘤）患者静脉输注顺铂（CDDP，80mg/m²）2小时和4小时后，未代谢顺铂的药代动力学参数与几种肾毒性标志物之间的关系进行定量分析。
采用特定的高效液相色谱法测定血浆和尿液中未代谢顺铂的水平。根据非房室模型计算药代动力学参数。在顺铂给药后30天内监测肾毒性标志物，包括血尿素氮（BUN）、血清肌酐（SCr）、血浆和尿液β2-微球蛋白（BMGp和BMGu）、尿N-乙酰-β-D-氨基葡萄糖苷酶（NAG）及肌酐清除率（CCR）。
2小时和4小时输注方案之间，未代谢顺铂的最大血浆浓度（Cmax）、最大尿排泄率（dAe/dt(max)）、血浆浓度-时间曲线下从零至无穷大的面积（AUC）、从零至无穷大的尿累积排泄量（Ae）、总清除率（Clt）、肾清除率（Clr）及血浆半衰期（t1/2）无显著差异。顺铂给药后，肾毒性标志物的值发生显著变化，提示顺铂化疗（80mg/m²）可导致肾毒性。未代谢顺铂的Cmax是肾毒性最具信息量的药代动力学参数。根据指数模型，在27次顺铂治疗中，Cmax与最大BUN、最大SCr及最低CCR水平相关。
为了在肾毒性最小的情况下实现更有效的顺铂化疗，目前的药代动力学和药效学研究表明，在2小时和4小时的标准持续输注方案中，未代谢顺铂的Cmax或稳态血浆水平应维持在1.5至2μg/ml之间。
