Doxorubicin (DOX) is a cytotoxic drug which has remained as an essential component of chemotherapy regiment for breast cancer. The cardiotoxicity of DOX is related to the accumulation of its main metabolite doxorubicinol (DOXOL) in the cardiac tissue. Although the pharmacokinetics of DOX shows high interindividual variability, there are no significant covariates to improve dose adjustment. The present study reports the pharmacokinetics of both DOX and DOXOL in a homogeneous population of young female patients with breast cancer (n = 12) making use of a standardized drug association, evaluated in the very first chemotherapy cycle, using plasma and urine data that allowed the calculation of the renal clearance of DOX, the formation clearance of DOXOL and the hepatic clearance of DOX. The extensive data availability also made it possible to estimate the hepatic extraction ratio of DOX for the investigated population, as well as to determine DOXOL unbound fraction in plasma for the first time in humans. DOX and DOXOL simultaneous analysis in plasma, plasma ultrafiltrate, and urine were performed by liquid chromatography coupled to mass spectrometry (LC-MS/MS). The pharmacokinetics profile of both DOX and DOXOL showed high variability (geometric coefficient of variation of area under the plasma concentration versus time curve extrapolated to infinity was approximately 215 %). The geometrics means were 0.26 for DOXOL/DOX AUC ratio, 15 % and 17 % for unbound fractions of DOX and DOXOL, respectively, 30.70 L⋅h-1 for total clearance, 0.66 L⋅h-1 for renal clearance, 29.97 L⋅h-1 for hepatic clearance and 0.39 L⋅h-1 for the formation clearance of the metabolite DOXOL. The 95 % confidence interval of the estimated hepatic extraction ratio of DOX ranged from 0.14 to 0.79, which characterizes DOX as a drug of low, intermediate or high hepatic extraction ratio.

中文翻译：

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乳腺癌患者中阿霉素的总，肾和肝清除率以及阿霉素的形成清除率：估算阿霉素肝提取率。

阿霉素（DOX）是一种细胞毒性药物，至今仍作为乳腺癌化疗方案的重要组成部分。DOX的心脏毒性与其主要代谢物阿霉素（DOXOL）在心脏组织中的积累有关。尽管DOX的药代动力学表现出很高的个体差异性，但尚无明显的协变量可改善剂量调整。本研究报告了使用标准化药物关联对DOX和DOXOL在均一的年轻女性乳腺癌患者（n = 12）中的药代动力学，在最初的化疗周期中使用血浆和尿液数据进行了评估计算DOX的肾脏清除率，DOXOL的形成清除率和DOX的肝清除率。广泛的数据可用性还使得有可能估计被调查人群的DOX肝提取率，并首次确定人血浆中的DOXOL未结合部分。通过液相色谱-质谱联用（LC-MS / MS）进行血浆，血浆超滤液和尿液中的DOX和DOXOL同时分析。DOX和DOXOL的药代动力学曲线均显示出较高的变异性（血浆浓度下面积的几何变化系数随时间曲线外推至无穷大约为215％）。几何平均值分别为DOXOL / DOX AUC比0.26，DOX和DOXOL未结合部分的15％和17％，总清除率30.70 L·h-1，肾清除率0.66 L⋅h-1、29.97L⋅肝清除率h-1，0。39L⋅h-1用于代谢产物DOXOL的形成清除。DOX估计肝提取率的95％置信区间为0.14至0.79，这表明DOX是低，中或高肝提取率的药物。