Duflot Thomas, Marie-Cardine Aude, Verstuyft Céline, Filhon Bruno, Pereira Tony, Massy-Guillemant Nathalie, Joannidès Robinson, Bellien Jérémy, Lamoureux Fabien
Department of Pharmacology, Rouen University Hospital, 1 rue de Germont, F 76000, Rouen, France.
Normandie Univ, UNIROUEN, Inserm U1096, Rouen University, 22 boulevard Gambetta, F 76000, Rouen, France.
Fundam Clin Pharmacol. 2018 Jun;32(3):337-342. doi: 10.1111/fcp.12345. Epub 2018 Jan 25.
Ifosfamide (IFA) is a potent alkylating antitumoral agent, but its use is limited by neurological side effects. IFA is a racemic mixture of two enantiomeric forms, R-IFA and S-IFA with a stereoselective metabolism by CYP3A4 and CYP2B6, leading either to bioactive or to toxic pathways. In three consecutive cases of pediatric patients who exhibited IFA-induced encephalopathy (IIE), genotyping of clinically relevant single-nucleotide polymorphisms associated with decreased CYP3A4 and CYP2B6 activities was performed. Genetic investigations revealed the presence of CYP2B6 rs4803419 (C>T) in one patient while the two others carried the CYP2B66 allelic variant. All patients carried CYP3A4 wild-type genotype (CYP3A41/*1). Because CYP2B6-deficient alleles may be responsible for an increased conversion of S-IFA into neurotoxic metabolites, screening for CYP2B6 polymorphisms may help to avoid IIE and improve clinical outcomes.
异环磷酰胺（IFA）是一种强效的烷化剂抗肿瘤药物，但其使用受到神经副作用的限制。IFA是两种对映体形式R-IFA和S-IFA的外消旋混合物，通过CYP3A4和CYP2B6进行立体选择性代谢，导致生物活性或毒性途径。在连续三例表现出IFA诱导的脑病（IIE）的儿科患者中，对与CYP3A4和CYP2B6活性降低相关的临床相关单核苷酸多态性进行了基因分型。基因研究显示，一名患者存在CYP2B6 rs4803419（C>T），而另外两名患者携带CYP2B66等位基因变体。所有患者均携带CYP3A4野生型基因型（CYP3A41/*1）。由于CYP2B6缺陷等位基因可能导致S-IFA向神经毒性代谢物的转化增加，筛查CYP2B6多态性可能有助于避免IIE并改善临床结果。
