PHARMACOKINETICS AND METABOLISM OF EPIDOXORUBICIN AND DOXORUBICIN IN HUMANS
PHARMACOKINETICS AND METABOLISM OF EPIDOXORUBICIN AND DOXORUBICIN IN HUMANS
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DOI：
10.1200/jco.1988.6.3.517
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发表时间：
1988-03-01
影响因子：
45.3
通讯作者：
PINEDO, HM
中科院分区：
文献类型：
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作者：
MROSS, K;MAESSEN, P;PINEDO, HM
阿霉素(DOX)、表柔比星(EPI)及其代谢物在血浆中的药代动力学研究在8名患者中进行，这8名患者接受两个顺序周期的40-56 mg/m2的这两种蒽环类药物的推注。与DOX相比，EPI组的终末半衰期和分布体积较小，而血浆清除量和累积尿排出量较大。DOX的主要代谢物是阿霉素(AOL)，其次是7-脱氧阿霉素(7d-Aolon)。仅EPI组有向葡萄糖醛酸苷的代谢。EPI代谢产物的曲线下面积(AUC)由大到小依次为E-Glu&Gt、Eolglu、7d-Aolon&Gt、Eol。EOL的AUC是其对应的AOL的一半。在EPI的情况下，7d-Aolon的AUC是相应代谢物DOX的两倍。细胞抑制代谢物AOL和EOL的末端半衰期相似，但长于其母药的相应值。葡萄糖醛酸苷(E-Glu，EOL-Glu)的半衰期与其母药的半衰期相似。与DOX和EPI相比，7D-Aolon的半衰期略短。在最初的48小时内，大约6.2%的EPI和5.9%的DOX由肾脏排泄。DOX组尿中可见AOL，EPI组尿中可见EOL、E-Glu和EOL-Glu。EPI及其代谢物的累积尿量为10.5%，DOX及其代谢物的累积尿量为6.9%。(7d)-苷元的血药浓度-时间曲线在注射后2~12h出现第二个峰值，提示缺乏鸟苷胺糖基的代谢物存在肠-肝循环。E-Glu和EOL-Glu分别在1.2h和1.9h时血药浓度最高。所有其他化合物在服用DOX和EPI后的第一分钟内达到最大血药浓度。在一名患者中观察到了偏离血浆动力学的现象，这可能是由于先前给药的原因。
Pharmacokinetics of doxorubicin (DOX), epidoxorubicin (EPI), and their metabolites in plasma have been performed in eight patients receiving 40 to 56 mg/m2 of both anthracyclines as a bolus injection in two sequential cycles. Terminal half-life and volume of distribution appeared to be smaller in case of EPI, whereas plasma clearance and cumulative urinary excretion was larger in comparison to DOX. The major metabolite of DOX was doxorubicinol (Aol) followed by 7-deoxy-doxorubicinol (7d-Aolon). Metabolism to glucuronides was found in case of EPI only. The area under the curves (AUC) of the metabolites of EPI decreased in the order of the glucoronides E-glu > Eolglu, 7d-Aolon > epirubicinol (Eol). The AUC of Eol was half of the value in its counterpart Aol. In the case of EPI, the AUC of 7d-Aolon was twice the level of that of the corresponding metabolite of DOX. The terminal half-lives of the cytostatic metabolites Aol and Eol were similar, but longer than the corresponding values of their parent drugs. Half-lives of the glucuronides (E-glu, Eol-glu) were similar to the half-life of their parent drug. 7d-Aolon had a somewhat shorter half-life in comparison to both DOX and EPI. Approximately 6.2% of EPI and 5.9% of DOX were excreted by the kidney during the initial 48 hours. Aol was found in the urine of patients treated with DOX, whereas Eol, E-glu, and Eol-glu were detected in urine of patients treated with EPI. The cumulative urinary excretion appeared to be 10.5% for EPI and its metabolites, and 6.9% for DOX and its metabolite. The plasma concentration v time curves of (7d)-aglycones showed a second peak between two and 12 hours after injection, suggesting an enterohepatic circulation for metabolites lacking the daunosamine sugar moiety. The plasma concentrations of the glucuronides were maximal at 1.2 hours for E-glu and 1.9 hours for Eol-glu. All other compounds reached their maximum plasma concentration during the first minutes after the administration of DOX and EPI. Deviating plasma kinetics were observed in one patient, probably due to prior drug administration.