Felder T B, McLean M A, Vestal M L, Lu K, Farquhar D, Legha S S, Shah R, Newman R A
Department of Medical Oncology, University of Texas M. D. Anderson Hospital and Tumor Institute, Houston 77030.
Drug Metab Dispos. 1987 Nov-Dec;15(6):773-8.
Pharmacokinetics and urinary excretion of Amonafide (5-amino-2-[2-(dimethylamine)ethyl]-1H-benz[de]isoquinoline-1,3-(2H)- dione) were examined in seven patients who were administered 400 mg/m2 of drug as a 30-min infusion on a daily schedule for 5 consecutive days. Amonafide concentrations in plasma and urine were determined using reversed phase HPLC. Amonafide was eliminated from plasma with a terminal half-life of 3.5 hr. Renal excretion accounted for 23% of the administered dose. Amonafide pharmacokinetic parameters after the initial dose (day 1) were similar to those calculated after the fifth daily dose. Amonafide undergoes a significant amount of metabolism and eight urinary metabolites have been identified using a thermospray liquid chromatography-mass spectrometry (LC/MS) technique. Various N-acetylated species appear to be the major metabolites, although no evidence of N-acetylation was found in urine obtained from two patients. Two of the primary metabolites, the N(N5)-acetyl and N'(N1)-oxide metabolites of Amonafide, were tested in vitro for cytotoxicity against P388 murine leukemia cells. In this test system, the N-acetyl metabolite was observed to be only slightly less cytotoxic than the parent compound. The N'-oxide of Amonafide, however, proved to be inactive. These results are discussed together with the pharmacokinetic and metabolism data of this new investigational antitumor drug.
对7名患者进行了氨萘非特（5-氨基-2-[2-(二甲胺基)乙基]-1H-苯并[de]异喹啉-1,3-(2H)-二酮）的药代动力学和尿排泄研究。这些患者按每日一次的给药方案，连续5天在30分钟内输注400mg/m²的药物。采用反相高效液相色谱法测定血浆和尿液中的氨萘非特浓度。氨萘非特从血浆中消除的终末半衰期为3.5小时。肾排泄占给药剂量的23%。初始剂量（第1天）后的氨萘非特药代动力学参数与第5日剂量后计算得到的参数相似。氨萘非特发生大量代谢，已采用热喷雾液相色谱-质谱（LC/MS）技术鉴定出8种尿代谢产物。尽管在两名患者的尿液中未发现N-乙酰化的证据，但各种N-乙酰化产物似乎是主要代谢产物。对两种主要代谢产物，即氨萘非特的N(N5)-乙酰化和N'(N1)-氧化代谢产物，进行了体外抗P388小鼠白血病细胞细胞毒性测试。在该测试系统中，观察到N-乙酰化代谢产物的细胞毒性仅略低于母体化合物。然而，氨萘非特的N'-氧化物被证明无活性。结合这种新型抗肿瘤药物的药代动力学和代谢数据对这些结果进行了讨论。
