Buice R G, Veit B C, McAlpin S E, Gurley B J, Sidhu P, Thais A C
Res Commun Chem Pathol Pharmacol. 1985 Jan;47(1):123-32.
The effects of total body irradiation followed by bone marrow transplantation on the disposition kinetics of intravenously-administered methotrexate have been studied in the Wistar-Furth rat. Eight test animals received total body irradiation (1000 rads) followed by intravenous administration of 3 X 10(8) bone marrow cells per kg body weight. Eight control animals were sham-irradiated and received an equal volume of blank suspension medium. One day after these treatments each rat received methotrexate (25 mg/kg) by rapid intravenous injection and serial blood samples were obtained over a 3 hour period. Serum methotrexate concentrations were measured by high performance liquid chromatography and pharmacokinetic parameters were calculated after NONLIN analysis of data. No significant differences were observed in total body clearances of test and control animals. As methotrexate in the rat is cleared predominantly by renal excretion of unchanged drug, these findings suggest that this process is not affected by radiation. Significantly larger volumes of distribution were observed in test animals. Increased extent of distribution in irradiated animals could be a result of a radiation-induced increase in membrane permeability and/or increased blood flow to irradiated areas. Future studies should assess the clinical significance of such findings.
在Wistar - Furth大鼠中研究了全身照射后进行骨髓移植对静脉注射甲氨蝶呤处置动力学的影响。八只试验动物接受全身照射（1000拉德），随后每千克体重静脉注射3×10⁸个骨髓细胞。八只对照动物接受假照射并给予等体积的空白悬浮培养基。在这些处理一天后，每只大鼠通过快速静脉注射给予甲氨蝶呤（25毫克/千克），并在3小时内采集系列血样。通过高效液相色谱法测定血清甲氨蝶呤浓度，并在对数据进行NONLIN分析后计算药代动力学参数。在试验动物和对照动物的全身清除率方面未观察到显著差异。由于大鼠体内的甲氨蝶呤主要通过原形药物经肾排泄清除，这些发现表明该过程不受辐射影响。在试验动物中观察到分布容积显著更大。受照射动物分布范围的增加可能是辐射诱导的膜通透性增加和/或流向受照射区域的血流量增加的结果。未来的研究应评估这些发现的临床意义。
