Rask C, Albertioni F, Schrøder H, Peterson C
Department of Paediatrics, University Hospital of Aarhus, Denmark.
Pediatr Hematol Oncol. 1996 Jul-Aug;13(4):359-67. doi: 10.3109/08880019609030842.
Oral mucositis is a common problem after high-dose methotrexate (HD-MTX) treatment. Our purpose was to identify factors associated with the development of mucositis in children with ALL who had no delayed elimination of methotrexate (MTX) according to the conventional criteria (p-MTX at 42 hours < 1 mumol/L and at 66 hours < 0.2 mumol/L). Pharmacokinetic studies of MTX and the metabolite 7-hydroxymethotrexate (7-OHMTX) in plasma and saliva were carried out in 13 children treated with HD-MTX (5-8 g/m2 intravenously over 24 hours for a total of 44 courses). Oral mucositis was evaluated according to the criteria of the World Health Organization. Mucositis was observed in 52% of the infusions. In 28 infusions with no delayed elimination of MTX 39% developed mucositis, which was found to correlate significantly with low systemic clearance of MTX during the infusion and a low p-7-OHMTX/p-MTX ratio at 66 hours after the start of infusion. The MTX concentration in saliva did not show any correlation with the development of mucositis. The present conventional criteria for high-risk MTX concentrations might need to be reevaluated because a high percentage of patients still suffer from oral toxicity despite "normal" elimination. A reduced ratio between the simultaneous concentrations of 7-OHMTX and MTX in plasma may be a possible mechanism of this "unpredictable" oral toxicity.
口腔黏膜炎是大剂量甲氨蝶呤（HD-MTX）治疗后的常见问题。我们的目的是确定在根据传统标准（42小时时血浆中甲氨蝶呤（MTX）浓度<1 μmol/L且66小时时<0.2 μmol/L）无MTX延迟清除的急性淋巴细胞白血病（ALL）儿童中，与黏膜炎发生相关的因素。对13例接受HD-MTX治疗（24小时内静脉注射5 - 8 g/m²，共44个疗程）的儿童进行了血浆和唾液中MTX及其代谢产物7 - 羟基甲氨蝶呤（7-OHMTX）的药代动力学研究。根据世界卫生组织的标准评估口腔黏膜炎。52%的输注出现了黏膜炎。在28例无MTX延迟清除的输注中，39%发生了黏膜炎，发现其与输注期间MTX的低全身清除率以及输注开始后66小时时低的血浆7-OHMTX/MTX比值显著相关。唾液中的MTX浓度与黏膜炎的发生无任何相关性。鉴于尽管“清除正常”仍有高比例患者遭受口腔毒性，目前关于高风险MTX浓度的传统标准可能需要重新评估。血浆中7-OHMTX和MTX同时浓度的降低比值可能是这种“不可预测”口腔毒性的一种可能机制。
