Clinical and pharmacologic reappraisal of dichloromethotrexate.
Clinical and pharmacologic reappraisal of dichloromethotrexate.
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二氯甲氨蝶呤的临床和药理学重新评价。
DOI：
10.1093/jnci/80.19.1547
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Donehower,RC
中科院分区：
文献类型：
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作者：
Hantel,A;Rowinsky,EK;Noe,DA;McGuire,WP;Grochow,LB;Vito,BL;Ettinger,DS;Donehower,RC
二氯甲氨蝶呤（DCMTX）在过去30年中一直是零星临床开发的主题。虽然DCMTX的开发是希望发现一种更有效的抗叶酸剂，但这种类似物的潜在药理学和毒理学优势已经引起了更大的兴趣。进行了每28天在第1、8和15天给予DCMTX的I期和药代动力学试验，以测试这些潜在的优势。该方案的最大耐受剂量为980 mg/m2。肝毒性是剂量限制性的。不适、骨髓抑制和粘膜炎也是主要的毒性作用。按照该方案给药的DCMTX后续II期研究的推荐剂量为785 mg/m2，对于体能状态不佳或既往接受过广泛治疗的患者，剂量降至625 mg/m2。大多数患者的血浆消失曲线是双相或三相的，尽管有几个患者表现出更复杂的动力学模式，表明有显著的肝肠循环。血浆消失曲线下面积的大小与DCMTX肝毒性的严重程度有关。消除动力学呈线性，平均血浆清除率为294 mL/min（范围：128-715）。DCMTX的药代动力学行为不支持其在局部灌注中优于甲氨蝶呤。DCMTX的主要非肾脏消除表明，当与肾毒性药物（如顺铂）联合使用时，它可能比甲氨蝶呤更有优势。然而，没有理由投入大量资源进一步评价DCMTX，除非确定其在抗肿瘤活性方面的显著优势。[J Natl Cancer Inst 88;80：1547-1553]
Dichloromethotrexate (DCMTX) has been the subject of sporadic clinical development for the last 30 years. Although DCMTX was developed in hopes of discovering a more potent antifolate, the potential pharmacologic and toxicologic advantages of the analog have become of greater interest. This phase I and pharmacokinetic trial of DCMTX given on days 1, 8, and 15 every 28 days was undertaken to test these potential advantages. The maximally tolerated dose on this schedule was 980 mg/m2. Hepatic toxicity was dose limiting. Malaise, myelosuppression, and mucositis were also major toxic effects. The recommended dose for subsequent phase II studies of DCMTX administered on this schedule is 785 mg/m2with a reduction to 625 mg/m2for patients with a poor performance status or extensive prior therapy. Plasma disappearance curves for most patients were biphasic or triphasic, although several demonstrated more complex kinetic patterns that suggested significant enterohepatic circulation. The magnitude of the area under the plasma disappearance curve was related to the severity of DCMTX-induced hepatotoxlcity. The elimination kinetics were linear, with a mean plasma clearance of 294 mL/min (range, 128–715). The pharmacokinetic behavior of DCMTX does not support its use over methotrexate in regional perfusion. DCMTX's primarily nonrenal elimination suggests that it may have an advantage over methotrexate when combined with nephrotoxic drugs such as cisplatin. However, there is little reason to commit major resources to further evaluation of DCMTX unless significant advantages in antineoplastic activity are identified. [J Natl Cancer Inst 88;80:1547–1553]