Plasma and cerebrospinal fluid pharmacokineties of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates
Plasma and cerebrospinal fluid pharmacokineties of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates
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DOI：
10.1158/1078-0432.ccr-04-1807
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发表时间：
2005-02-15
影响因子：
11.5
通讯作者：
Balis, FM
中科院分区：
文献类型：
--
作者：
Jacobs, SS;Fox, E;Balis, FM
目的：描述并比较铂类似物、顺铂、卡铂和奥沙利铂的中枢神经系统药理学，并开发药代动力学模型来区分活性药物与惰性铂物质的处置。实验设计：草酸铂（7或5 mg/kg）、顺铂（2 mg/kg）、或卡铂（10 mg/kg）静脉内给药。在24小时内收集系列血浆和脑脊液（CSF）样品。立即制备血浆超滤。使用原子吸收光谱法测量铂浓度。使用线性梯形法推导浓度x时间曲线下面积。CSF渗透定义为CSF AUC（0.24）/血浆超滤液AUC（0.24）比值。A四室模型与一阶速率常数拟合的数据，以区分活性药物从非活性metabolites.Results：奥沙利铂，顺铂，卡铂的血浆超滤液的平均+/- SD AUC分别为61 - 22，18 +/- 6，和211 +/- 64 mumol/L小时，分别。奥沙利铂、顺铂和卡铂的CSF AUC分别为1.2 +/- 0.4 mumol/L小时、0.56 +/- 0.08 mumol/L小时和8 +/- 2.2 mumol/L小时，CSF渗透率分别为2.0%、3.6%和3.8%。对于奥沙利铂、顺铂和卡铂，药代动力学模型估计活性药物分别占血浆超滤液中铂的29%、79%和81%，CSF中铂的25%、89%和56%。奥沙利铂、顺铂和卡铂的活性药物的CSF渗透率分别为1.6%、3.7%和2.6%。结论：铂类似物的CSF渗透是有限的。药代动力学模型区分了血浆和CSF中的活性药物及其非活性（惰性）代谢产物。
Purpose: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species.Experimental Design: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration x time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC(0.24)/plasma ultrafiltrate AUC(0.24) ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites.Results: The mean +/- SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 22, 18 +/- 6, and 211 +/- 64 mumol/L hour, respectively. The AUCs in CSF were 1.2 +/- 0.4 mumol/L hour for oxaliplatin, 0.56 +/- 0.08 mumol/L hour for cisplatin, and 8 +/- 2.2 mumol/L hour for carboplatin, and CSF penetration was 2.0 %, 3.6 %, and 3.8 %, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29 %, 79 %, and 81 % of platinum in plasma ultrafiltrate, respectively, and 25 %, 89 %, and 56 % of platinum in CSF, respectively. The CSF penetration of active drug was 1.6 % for oxaliplatin, 3.7 % for cisplatin, and 2.6 % for carboplatin.Conclusions: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF.