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首页> 外文期刊>Journal of Pharmaceutical and Biomedical Analysis: An International Journal on All Drug-Related Topics in Pharmaceutical, Biomedical and Clinical Analysis >Total, renal and hepatic clearances of doxorubicin and formation clearance of doxorubicinol in patients with breast cancer: Estimation of doxorubicin hepatic extraction ratio
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Total, renal and hepatic clearances of doxorubicin and formation clearance of doxorubicinol in patients with breast cancer: Estimation of doxorubicin hepatic extraction ratio

机译：乳腺癌患者患者的多柔比星和多柔比霉素形成清除的总，肾和肝脏间隙：估计多柔比星肝提取率

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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. (C) 2020 Elsevier B.V. All rights reserved.
机译：Doxorubicin（Dox）是一种细胞毒性药物，其作为乳腺癌化疗团的重要组成部分。 Dox的心脏毒性与心脏组织中其主要代谢物多柔霉素（Doxol）的积累有关。虽然DOX的药代动力学显示出高的接口变异性，但没有显着的协变量来改善剂量调节。本研究报告了Dox和Doxol两种雌性乳腺癌（n = 12）的均匀群体中的药代动力学，所述乳腺癌（n = 12）利用标准化药物协会，在第一种化疗周期中评价，使用允许的血浆和尿液数据DOX肾间隙的计算，DOX的形成清除和DOX的肝脏清除。广泛的数据可用性也使得可以估计DOX的肝提取率为所研究的群体，以及在人类中首次确定血浆中的Doxol未结合级别。通过液相色谱法偶联至质谱法（LC-MS / MS）进行DOX和Doxol同时分析等离子体，血浆超滤和尿液。 DOX和Doxol的药代动力学曲线显示出高变异性（等离子体浓度下面积的几何变异系数与时间曲线外推到无穷大约215％）。对于多X和DOX AUC比率的几何方法为0.26，对于DOX和DOXOL的未结级分，30.70 LH（-1），肾间隙的0.66 LH（-1），29.97 LH（ -1）用于肝脏间隙和0.39 LH（-1）用于代谢物Doxol的形成间隙。估计的肝提取比的95％置信区间的DOX的范围为0.14至0.79，其表征DOX作为低，中间或高肝提取率的药物。 （c）2020 Elsevier B.v.保留所有权利。

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