He Y L, Tanigawara Y, Yasuhara M, Hori R
Department of Pharmacy, Kyoto University Hospital, Faculty of Medicine, Japan.
Drug Metab Dispos. 1991 Jul-Aug;19(4):729-34.
The effect of folinic acid (CF) on the tissue residence and renal excretion of methotrexate (MTX) in the rat model is described in an experiment designed to resemble a clinical regimen of high-dose MTX therapy with CF rescue. Concentrations of MTX in the kidney, liver, and plasma were determined following the sequential killing of the animals up to 24 hr after an iv bolus injection of 100 mumol/kg MTX. The treated group received repeated iv doses of CF (5.86 mumol/kg) for 9.3 hr. The tissue retention property of MTX was characterized by noncompartmental parameters, the mean residence time (MRT), and the single-pass mean residence time (MRTSP) in organs. The values of MRT in the kidney and liver were greater than that in plasma and were shortened by the CF treatment, indicating that CF is effective in reducing the duration of exposure to MTX in those organs. For drugs whose duration of exposure is a key factor in their toxicity, MRTSP was shown to be a useful parameter in toxicokinetic study. The renal clearance of MTX was virtually constant over a wide range of plasma MTX levels (0.1-165 microM) and was inhibited by p-aminohippurate. CF accelerated the renal excretion of MTX, which effect depended on the plasma concentration of MTX. Since reabsorption and filtration were not affected by CF, the increased excretion of MTX was attributed to a stimulation of tubular secretion. These observations show that CF exerts a beneficial effect in accelerating the excretion of MTX residing in the organs, in addition to supplying active folate to aid the resumption of de novo DNA synthesis.
在一项旨在模拟高剂量甲氨蝶呤（MTX）治疗联合亚叶酸钙（CF）解救的临床方案的实验中，描述了CF对大鼠模型中甲氨蝶呤（MTX）的组织滞留和肾脏排泄的影响。在静脉推注100 μmol/kg MTX后，对动物进行序贯处死，直至24小时，测定肾脏、肝脏和血浆中的MTX浓度。治疗组接受重复静脉注射CF（5.86 μmol/kg），持续9.3小时。MTX的组织滞留特性通过非房室参数、平均滞留时间（MRT）和器官中的单通道平均滞留时间（MRTSP）来表征。肾脏和肝脏中的MRT值大于血浆中的MRT值，并且通过CF治疗而缩短，这表明CF可有效减少这些器官中MTX的暴露持续时间。对于暴露持续时间是其毒性关键因素的药物，MRTSP被证明是毒代动力学研究中的一个有用参数。MTX的肾脏清除率在广泛的血浆MTX水平（0.1 - 165 μM）范围内几乎恒定，并受到对氨基马尿酸的抑制。CF加速了MTX的肾脏排泄，其作用取决于MTX的血浆浓度。由于重吸收和滤过不受CF影响，MTX排泄增加归因于肾小管分泌的刺激。这些观察结果表明，CF除了提供活性叶酸以帮助重新开始从头合成DNA外，还在加速器官中MTX的排泄方面发挥有益作用。
