Gamelin E, Bouil A L, Boisdron-Celle M, Turcant A, Delva R, Cailleux A, Krikorian A, Brienza S, Cvitkovic E, Robert J, Larra F, Allain P
Department of Medical Oncology and Clinical Pharmacology, Centre Paul Papin, Centre Regional de Lutte Contre le Cancer, 49033 Angers Cedex.
Clin Cancer Res. 1997 Jun;3(6):891-9.
The cumulative pharmacokinetic pattern of oxaliplatin, a new diamminecyclohexane platinum derivative, was studied in patients with metastatic colorectal cancer. Oxaliplatin was administered by i. v. infusion (130 mg/m2) over 2 h every 3 weeks, and 5-fluorouracil and leucovorin were administered weekly. A very sensitive method, inductively coupled plasma-mass spectrometry, allowed for the determination of total plasma and ultracentrifugable (UC) and RBC platinum levels on day 1, at 0, 2, and 5 h, and on days 8, 15, and 22. Sixteen patients underwent three or more courses, and six of them underwent six or more courses. The platinum concentration curves were quite similar from one course to another, with a high peak value 2 h after administration (day 1, Cmax = 3201 +/- 609 microgram/liter) and a rapid decrease (day 8, 443 +/- 99 microgram/liter). Cmax of both total and UC platinum levels in plasma remained unchanged throughout the treatment. The mean total platinum half-life in plasma was 9 days. We found residual levels of total platinum on day 22 (161 +/- 45 microgram/liter), but we observed no significant accumulation for the four first cycles (P = 0.57). In contrast, platinum accumulated significantly in RBCs after three courses (+91% at day 22 of the third cycle versus day 22 of the first cycle, P = 0.000018), and its half-life there was equivalent to that of RBCs. The patterns of UC and total platinum concentration curves were very similar and correlated significantly (P < 10(-6)) at all sampling times. The mean UC:total platinum ratio was 15% at day 1 and 5% at days 8, 15, and 22 in the 3-week treatment course. Unlike cisplatin, which rapidly accumulates in plasma as both free and bound platinum, oxaliplatin does not accumulate in plasma, but it does accumulate in RBCs, after repeated cycles at the currently recommended dose (130 mg/m2) and schedule of administration (every 3 weeks).
对一种新型二胺环己烷铂衍生物奥沙利铂在转移性结直肠癌患者中的累积药代动力学模式进行了研究。奥沙利铂每3周静脉输注130mg/m²，持续2小时，5-氟尿嘧啶和亚叶酸钙每周给药。一种非常灵敏的方法，即电感耦合等离子体质谱法，可用于测定第1天、0、2和5小时以及第8、15和22天的血浆总铂、超速离心可分离（UC）铂和红细胞铂水平。16例患者接受了三个或更多疗程，其中6例接受了六个或更多疗程。各疗程的铂浓度曲线彼此非常相似，给药后2小时出现高峰值（第1天，Cmax = 3201±609μg/升），随后迅速下降（第8天，443±99μg/升）。整个治疗过程中血浆总铂和UC铂水平的Cmax保持不变。血浆中总铂的平均半衰期为9天。我们在第22天发现了总铂的残留水平（161±45μg/升），但在最初四个周期中未观察到明显蓄积（P = 0.57）。相比之下，三个疗程后铂在红细胞中显著蓄积（第三个周期第22天比第一个周期第22天增加91%，P = 0.000018），其在红细胞中的半衰期与红细胞的半衰期相当。UC铂和总铂浓度曲线的模式非常相似，在所有采样时间均显著相关（P < 10⁻⁶）。在3周的治疗疗程中，第1天UC:总铂的平均比值为15%，第8、15和22天为5%。与顺铂不同，顺铂作为游离铂和结合铂在血浆中迅速蓄积，而奥沙利铂在血浆中不蓄积，但在按照当前推荐剂量（130mg/m²）和给药方案（每3周一次）重复给药后，会在红细胞中蓄积
