Albertioni F, Rask C, Schroeder H, Peterson C
Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
Anticancer Drugs. 1997 Feb;8(2):119-24. doi: 10.1097/00001813-199702000-00003.
The purpose of the study was to find out if saliva concentrations of methotrexate (MTX) and its main metabolite, 7-hydroxymethotrexate (7-OHMTX), can predict oral mucositis in children with acute lymphoblastic leukemia (ALL) after treatment with high-dose consolidation therapy. We have also studied the relationship between the concentrations of MTX and 7-OHMTX in saliva and the unbound concentrations in plasma. Twelve patients (36 infusions) were studied during treatment with high-dose MTX as remission consolidation therapy (5-8 g/m2 by 24 h i.v. infusion followed by leucovorin rescue). Plasma and saliva concentrations of MTX and 7-OHMTX were determined concomitantly by HPLC at 20 h and at various times following infusion. Unbound plasma concentrations of MTX and 7-OHMTX were determined after ultrafiltration. Oral toxicity was graded according to the WHO criteria (grade 0-4). The concentrations of MTX and 7-OHMTX in saliva were not directly related to the development of mucositis. In patients with oral mucositis (WHO grade 1 or greater), the ratio to 7-OHMTX and MTX in saliva at 20 h was significantly lower than in patients without symptoms (p = 0.014, Mann Whitney rank sum test), but not at 42 and 66 h after starting the infusion. The salivary concentration of 7-OHMTX at 20 h ranged from undetectable (less than 1 nmol/l) to 1.6 micromol/l. No significant correlation was found between the unbound and total plasma concentrations of MTX and 7-OHMTX and the drug concentrations in saliva at different points in time. The concentrations of 7-OHMTX in saliva were 11, 23 and 13% of the unbound plasma concentrations at 20, 42 and 66 h, respectively, after starting the infusion. The respective median corresponding values for MTX were 1.6, 16.1 and 61.6%. The results suggest that determinations of saliva concentrations of MTX and 7-OHMTX may predict oral mucositis. This opens up the possibility of early identification of patients at high risk of developing oral mucositis in order to intensify topical or systemic treatment of these patients.
本研究的目的是探究甲氨蝶呤（MTX）及其主要代谢产物7-羟基甲氨蝶呤（7-OHMTX）的唾液浓度是否能够预测急性淋巴细胞白血病（ALL）患儿在接受大剂量巩固治疗后的口腔黏膜炎。我们还研究了唾液中MTX和7-OHMTX的浓度与血浆中游离浓度之间的关系。在12例患者（36次输注）接受大剂量MTX作为缓解巩固治疗期间（通过24小时静脉输注5-8 g/m²，随后进行亚叶酸钙解救）进行了研究。在输注后20小时及不同时间点，通过高效液相色谱法（HPLC）同时测定MTX和7-OHMTX的血浆和唾液浓度。超滤后测定MTX和7-OHMTX的血浆游离浓度。根据世界卫生组织标准（0-4级）对口腔毒性进行分级。唾液中MTX和7-OHMTX的浓度与口腔黏膜炎的发生没有直接关系。在患有口腔黏膜炎（世界卫生组织1级或更高等级）的患者中，20小时时唾液中7-OHMTX与MTX的比值显著低于无症状患者（p = 0.014，曼-惠特尼秩和检验），但在开始输注后42小时和66小时并非如此。20小时时7-OHMTX的唾液浓度范围为不可检测（低于1 nmol/l）至1.6 μmol/l。在不同时间点，MTX和7-OHMTX的血浆游离浓度与总浓度以及唾液中的药物浓度之间未发现显著相关性。开始输注后，20、42和66小时时唾液中7-OHMTX的浓度分别为血浆游离浓度的11%、23%和13%。MTX的相应中位数对应值分别为1.6%、16.1%和61.6%。结果表明，测定唾液中MTX和7-OHMTX的浓度可能预测口腔黏膜炎。这为早期识别有发生口腔黏膜炎高风险的患者提供了可能性，以便加强对这些患者的局部或全身治疗。
