Division of Pharmacy, MD Anderson Cancer Center, Houston, TX, USA.
Ann Pharmacother. 2011 Jul;45(7-8):e39. doi: 10.1345/aph.1Q087. Epub 2011 Jul 5.
To report the case of a clinically significant drug interaction between intravenous busulfan and oral metronidazole observed through busulfan therapeutic drug monitoring (TDM).
A 7-year-old boy with a history of myelodysplasia that progressed to acute myeloid leukemia received busulfan with therapeutic drug monitoring (TDM), clofarabine, and thiotepa as a pretransplant conditioning regimen for a cord blood transplant. The patient received metronidazole the day after a busulfan test dose of 0.5 mg/kg was administered. On the day of the first busulfan therapeutic dose, TDM was performed and the clearance of busulfan was significantly decreased by 46%. After 2 doses of busulfan therapy, the course area under the curve was exceeded, requiring discontinuation of busulfan. Metronidazole is not known to affect glutathione or the glutathione S-transferase A1 (GSTA1) enzyme system or cytochrome P450 (CYP) 3A4.
Busulfan is a bifunctional alkylating agent widely used in pretransplant conditioning regimens in patients undergoing stem cell transplantation for hematologic malignancies. Busulfan metabolism is best described by hepatic conjugation to glutathione by GSTA1, although some CYP-dependent pathways have been described. Currently there is 1 publication describing the drug interaction between oral busulfan and oral metronidazole, in which concomitant use of metronidazole resulted in higher busulfan trough concentrations and higher risk of veno-occlusive disease. Our case represents a possible drug interaction based on the Horn Drug Interaction Probability Scale.
Though the mechanistic basis for this interaction is unknown, the risks and benefits of using metronidazole during and in close proximity to busulfan should be carefully considered and therapeutic alternatives to metronidazole should be used when appropriate.
报告一例通过静脉注射白消安治疗药物监测（TDM）发现的白消安与口服甲硝唑之间具有临床意义的药物相互作用。
一名 7 岁男孩患有骨髓增生异常综合征，进展为急性髓系白血病，在接受脐带血移植前，接受了白消安 TDM、克拉屈滨和噻替哌的治疗。患者在给予 0.5mg/kg 白消安测试剂量的第二天接受了甲硝唑治疗。在给予第一个白消安治疗剂量的当天，进行了 TDM，发现白消安清除率显著下降了 46%。在给予 2 个剂量的白消安治疗后，曲线下面积超过了治疗范围，需要停止白消安治疗。甲硝唑已知不会影响谷胱甘肽或谷胱甘肽 S-转移酶 A1（GSTA1）酶系统或细胞色素 P450（CYP）3A4。
白消安是一种双功能烷化剂，广泛用于接受造血系统恶性肿瘤干细胞移植的患者的移植前预处理方案中。白消安的代谢最好通过 GSTA1 将谷胱甘肽结合来描述，尽管已经描述了一些 CYP 依赖性途径。目前有 1 篇文献描述了口服白消安和口服甲硝唑之间的药物相互作用，其中同时使用甲硝唑会导致白消安谷浓度升高和静脉闭塞性疾病风险增加。我们的病例代表了基于 Horn 药物相互作用可能性量表的可能的药物相互作用。
尽管这种相互作用的机制尚不清楚，但在使用白消安期间和在其附近使用甲硝唑的风险和益处应仔细考虑，并在适当情况下应使用甲硝唑的治疗替代药物。
