COMPARATIVE PHARMACOKINETICS OF ESCALATING DOSES OF DOXORUBICIN IN PATIENTS WITH METASTATIC BREAST-CANCER
COMPARATIVE PHARMACOKINETICS OF ESCALATING DOSES OF DOXORUBICIN IN PATIENTS WITH METASTATIC BREAST-CANCER
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DOI：
10.1007/bf00686055
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发表时间：
1990-01-01
影响因子：
3
通讯作者：
WILKINSON, PM
中科院分区：
文献类型：
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作者：
BRONCHUD, MH;MARGISON, JM;WILKINSON, PM
重组人粒细胞集落刺激因子（G-CSF）已被证明可以减少细胞毒性治疗后的中性粒细胞减少，从而使剂量递增，以提高反应率。了解药物动力学是否随剂量增加而改变是很重要的。选择多柔比星是因为其广谱活性和已知的转移性乳腺癌疗效。75，100，125和150毫克/平方米的剂量给予11例转移性乳腺癌患者输注超过30分钟。母体药物和代谢产物的血清浓度测定在第一个48小时后，通过高效液相色谱法（HPLC）输注。血药浓度-时间曲线在4例患者中呈三指数函数衰减，7例患者呈双指数函数衰减。四房室模型（中央和三个外周）预测浓度在观察值的1 SE范围内。多柔比星是主要代谢产物，并明确鉴定了多柔比星酮和7-脱氧多柔比星酮。AUC. inf呈线性增加。剂量。此外，在给予多柔比星后6 h，观察到多柔比星和其他重要代谢物的循环水平出现小幅一过性升高，这表明存在肝肠或其他再循环机制。我们得出结论，在选定的剂量范围内，阿霉素的动力学是线性的，并且在第二次和第三次两周给药后，在较高剂量的阿霉素下观察到的毒性增加可能是由于组织中的细胞内药物蓄积。
Recombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m2 were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, on central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was linear increase in the AUC.infin. with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.