Jakobsen P, Sørensen B, Bastholt L, Mirza M R, Gjedde S B, Mouridsen H T, Rose C
Institute of Pharmacology, University of Aarhus, Denmark.
Cancer Chemother Pharmacol. 1994;35(1):45-52. doi: 10.1007/BF00686283.
A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-microns silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600-1000 mg/m2) together with different doses of epirubicin (E, 60-100 mg/m2), fixed-dose cyclophosphamide (C, 600 mg/m2), fixed-dose 5-fluorouracil (F, 600 mg/m2), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m2. We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.
已开发出一种高压液相色谱法，用于测定双二氧哌嗪衍生物ADR - 529（ICRF - 187），该化合物已被证明在预防蒽环类药物引起的心脏毒性方面有效。使用窄孔5微米硅胶柱和紫外检测时，定量限为5纳克/毫升。该方法用于测定在转移性乳腺癌患者治疗中，每三周静脉注射不同剂量的ADR - 529（600 - 1000毫克/平方米）与不同剂量表柔比星（E，60 - 100毫克/平方米）、固定剂量环磷酰胺（C，600毫克/平方米）、固定剂量5 - 氟尿嘧啶（F，600毫克/平方米）以及每日服用他莫昔芬（T，30毫克；CEF - T）后ADR - 529的药代动力学特征。还测定了表柔比星的药代动力学参数。该研究的目的是确定：（1）作为CEF - T联合用药一部分的ADR - 529的药代动力学是否会随着ADR - 529剂量增加和表柔比星剂量增加而改变；（2）在相同联合用药中，随着ADR - 529剂量增加，表柔比星的药代动力学是否会改变。总共纳入了82名患者。一项包括16名患者的交叉研究表明，表柔比星与ADR - 529同时给药或不伴随给药时，其药代动力学参数无显著差异。除分布半衰期有轻微变化外，随着ADR - 529剂量增加，表柔比星的药代动力学参数未改变，ADR - 529自身的药代动力学参数也未改变。除了当表柔比星剂量从60毫克/平方米提高到100毫克/平方米时，末端半衰期增加30%和全身清除率降低外，表柔比星剂量递增并未显著改变ADR - 529的药代动力学参数。我们得出结论，在适合预防蒽环类药物引起的心脏毒性的剂量下，同时给予ADR - 529不会改变表柔比星的分布和消除。
