Pharmacokinetics and Toxicodynamics of Oxaliplatin in Rats: Application of a Toxicity Factor to Explain Differences in the Nephrotoxicity and Myelosuppression Induced by Oxaliplatin and the Other Platinum Antitumor Derivatives
Pharmacokinetics and Toxicodynamics of Oxaliplatin in Rats: Application of a Toxicity Factor to Explain Differences in the Nephrotoxicity and Myelosuppression Induced by Oxaliplatin and the Other Platinum Antitumor Derivatives
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DOI：
10.1007/s11095-010-0189-4
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发表时间：
2010-09-01
影响因子：
3.7
通讯作者：
Ogata, Hiroyasu
中科院分区：
文献类型：
--
作者：
Hanada, Kazuhiko;Suda, Makoto;Ogata, Hiroyasu
目的我们以前报道过，血浆浓度-时间曲线下面积（AUC（p））和毒性因子（定义为组织与血浆浓度的表观比值（Kp（app））和表观水解速率常数（k（水解））的乘积）是铂类药物顺铂、卡铂和奈达铂诱导的不同程度毒性的决定因素。方法采用大鼠静脉推注和静脉滴注奥沙利铂，测定其药代动力学线性、总清除率和稳态Kp（app）。在体外测定K（水解）。结果血小板计数呈剂量依赖性下降，但血尿素氮（BUN）无明显升高。奥沙利铂和其他三种铂类药物引起的血小板计数降低程度不能通过AUC（p）和骨髓AUC的差异来解释，但可以通过AUC（p）和毒性因子的组合来拟合（r = 0.908，结论AUC（p）的乘积并且毒性因子是奥沙利铂毒性程度的有用预测因子，正如在其它铂类药物中观察到的那样。
Purpose We previously reported that the product of the area under the plasma concentration-time curve (AUC(p)) and a toxicity factor, which in turn was defined as the product of the apparent ratio of tissue to plasma concentration (Kp(app)) and the apparent hydrolysis rate constant (k(hydrolysis)), was a determinant of the different degrees of toxicities induced by platinum drugs, cisplatin, carboplatin and nedaplatin. We tested this model with oxaliplatin.Methods Oxaliplatin was administered to rats by intravenous bolus or infusion, and the linearity of pharmacokinetics, total clearance and the Kp(app) at steady state were determined. k(hydrolysis) was determined in vitro. Nephrotoxicity was estimated from blood urea nitrogen (BUN) level and myelosuppression from platelet count.Results The platelet count decreased dose-dependently, but BUN did not increase significantly. The degree of decrease in platelet count caused by oxaliplatin and the other three platinum drugs was not explained by the differences of AUC(p) and AUC for the bone marrow but was fitted by a combination of AUC(p) and the toxicity factor (r = 0.908, P < 0.001).Conclusions The product of AUC(p) and the toxicity factor is a useful predictor of the degree of toxicity of oxaliplatin as has been observed with other platinum drugs.