van Hennik M B, van der Vijgh W J, Klein I, Elferink F, Vermorken J B, Winograd B, Pinedo H M
Department of Oncology, Free University Hospital, Amsterdam, The Netherlands.
Cancer Res. 1987 Dec 1;47(23):6297-301.
Pharmacokinetics of cisplatin, spiroplatin, ethylenediaminemalonatoplatinum(II) (JM-40), and carboplatin was studied in BALB/c x DBA/2 F1 mice receiving 10% lethal doses of 15.5, 6.8, 100, and 165 mg/kg, respectively. Blood samples were collected for up to 5 days after a single i.v. bolus injection. Total platinum in plasma and non-protein-bound free platinum in plasma ultrafiltrate were determined by flameless atomic absorption spectrometry. Parent JM-40 and carboplatin were determined by high performance liquid chromatography. Calculated pharmacokinetic parameters (peak concentrations, half-lives, areas under the curve) were compared with the corresponding values in patients at the maximal tolerated dose. Peak plasma concentrations were 2.4- to 20-fold higher in mice than in humans. Initial and terminal half-lives in mice were up to 6 times shorter than in patients. However, the areas under the plasma concentration versus time curves (AUCs) were found to agree. The ratios of the AUCs of free platinum in patients (AUCp) and mice (AUCm) measured over the first part of the plasma concentration versus time curve were 1.2, 0.3, 1.1, and 0.9 for cisplatin, spiroplatin, JM-40, and carboplatin, respectively. These values changed to 1.3, 0.3, 2.5, and 1.0 when the time interval was extended to free platinum levels just above the detection limit. Ratios of the AUCs of total platinum in patients and mice measured over 5 days were 2.7, 2.6, 4.2, and 1.8, respectively. Using a ratio of 1 for free platinum originating from JM-40, the retrospectively calculated maximal tolerated dose from AUCp at low dosages was 1021 mg/m2 (n = 7; range, 836-1282), compared to 1200 mg/m2 as found in the phase I trial. This suggests that the AUCp/AUCm ratio of free platinum over the first part of the concentration versus time curve can possibly be used to predict the maximal tolerated dose of platinum analogues in humans, during the early stage of phase I studies.
在分别接受15.5、6.8、100和165mg/kg 10%致死剂量的BALB/c×DBA/2 F1小鼠中研究了顺铂、螺铂、乙二胺丙二酸铂（II）（JM-40）和卡铂的药代动力学。单次静脉推注后，最多5天内采集血样。采用无火焰原子吸收光谱法测定血浆中的总铂和血浆超滤液中的非蛋白结合游离铂。采用高效液相色谱法测定母体JM-40和卡铂。将计算得到的药代动力学参数（峰值浓度、半衰期、曲线下面积）与患者在最大耐受剂量时的相应值进行比较。小鼠的血浆峰值浓度比人类高2.4至20倍。小鼠的初始半衰期和终末半衰期比患者短达6倍。然而，发现血浆浓度-时间曲线下面积（AUC）是一致的。在血浆浓度-时间曲线的第一部分测量的患者（AUCp）和小鼠（AUCm）游离铂的AUC比值，顺铂、螺铂、JM-40和卡铂分别为1.2、0.3、1.1和0.9。当时间间隔延长至游离铂水平刚好高于检测限时，这些值变为1.3、0.3、2.5和1.0。在5天内测量的患者和小鼠总铂的AUC比值分别为2.7、2.6、4.2和1.8。以JM-40产生的游离铂的比值为1，根据低剂量时的AUCp回顾性计算的最大耐受剂量为1021mg/m2（n = 7；范围，836 - 1282），而在I期试验中为1200mg/m2。这表明，在I期研究的早期阶段，浓度-时间曲线第一部分的游离铂的AUCp/AUCm比值可能可用于预测人类铂类类似物的最大耐受剂量。
