Raynaud F I, Mistry P, Donaghue A, Poon G K, Kelland L R, Barnard C F, Murrer B A, Harrap K R
Institute of Cancer Research, CRC Centre for Cancer Therapeutics, Sutton, Survey, UK.
Cancer Chemother Pharmacol. 1996;38(2):155-62. doi: 10.1007/s002800050464.
This study evaluates the metabolic profile of JM216 [bis(acetato)ammine-dichloro(cyclohexylamine) platinum(IV)], the first orally administrable platinum complex, in plasma ultrafiltrates of 12 patients (n = 2-4 time points per patient) following different doses of drug (120, 200, 340, 420, 560 mg/m2). The biotransformation profile was evaluated by high-performance liquid chromatography (HPLC) followed by atomic absorption spectrophotometry (AA). The AA profiles were compared with those previously identified by HPLC on line with mass spectrometry (HPLC-MS) in plasma incubated with JM216. A total of six platinum peaks (Rt = 5.5, 7.2, 10.6, 12.4, 15.6, and 21.6 min, respectively) were observed in patients' plasma ultrafiltrate samples, of which only four appeared during the first 6 h post-treatment. Four of these coeluted with those observed and identified previously in plasma incubation medium. No parent JM216 was detected. The major metabolite seen in patients was the Pt II complex JM118 [cis-amminedichloro-(cyclohexylamine)platinum(II)] and was observed in all the patients. Interestingly, the second metabolite was shown to coelute with the Pt IV species JM383 [bis-acetatoammine(cyclohexylamine)dihydroxoplatinum (IV)]. Both JM118 and JM383 were identified by HPLC-MS in a clinical sample. Peak C, which was a minor product (less than 5% of the free platinum), coeluted with JM559 [bis-acetatoammine-chloro(cyclohexylalamine)hydroxoplatin um(IV)]. The cytotoxicity profile of all three metabolites in a panel of cisplatin-sensitive and -resistant human ovarian carcinoma cell lines was very close to that of the parent drug. In addition, the concentrations of JM118 reached in patients' plasma ultrafiltrate were comparable with the cytotoxic levels of the compound determined in the ovarian carcinoma panel of cell lines. Two metabolites were seen in patients but not in the in vitro incubation medium, suggesting the involvement of a possible enzymatic reaction. Thus, the biotransformation profile following oral administration of JM216 shows a variety of Pt(IV) and Pt(Il) metabolites in plasma that differ significantly from other systemically applied platinum drugs.
本研究评估了首个可口服的铂配合物JM216[双(乙酸根)氨-二氯(环己胺)铂(IV)]在12例患者（每位患者有2至4个时间点）不同剂量药物（120、200、340、420、560mg/m²）后的血浆超滤液中的代谢情况。通过高效液相色谱法（HPLC）继以原子吸收光谱法（AA）评估生物转化情况。将AA图谱与先前在与JM216孵育的血浆中通过HPLC与质谱联用（HPLC-MS）鉴定的图谱进行比较。在患者血浆超滤液样本中总共观察到6个铂峰（保留时间分别为5.5、7.2、10.6、12.4、15.6和21.6分钟），其中只有4个在治疗后6小时内出现。其中4个与先前在血浆孵育介质中观察到并鉴定的峰共洗脱。未检测到母体JM216。患者体内观察到的主要代谢物是铂(II)配合物JM118[顺-氨二氯(环己胺)铂(II)]，且在所有患者中均有观察到。有趣的是，第二种代谢物显示与铂(IV)物质JM383[双乙酸根氨(环己胺)二羟基铂(IV)]共洗脱。JM118和JM383均通过临床样本中的HPLC-MS鉴定。峰C是次要产物（占游离铂的比例小于5%），与JM559[双乙酸根氨-氯(环己胺)羟基铂(IV)]共洗脱。在一组顺铂敏感和耐药的人卵巢癌细胞系中，所有三种代谢物的细胞毒性情况与母体药物非常接近。此外，患者血浆超滤液中达到的JM118浓度与在卵巢癌细胞系组中测定的该化合物的细胞毒性水平相当。在患者体内观察到两种代谢物，但在体外孵育介质中未观察到，这表明可能涉及酶促反应。因此，口服JM216后的生物转化情况显示血浆中存在多种铂(IV)和铂(II)代谢物，这与其他全身应用的铂类药物有显著差异。
