Lui C Y, Lee M G, Chiou W L
Cancer Res. 1985 Apr;45(4):1545-8.
Plasma, renal, and nonrenal clearances of methotrexate as well as their interrelationship were studied in five conditioned male beagle-mongrel dogs using the multiple-rate infusion method. Steady-state plasma methotrexate concentrations of 1, 20, and 100 micrograms/ml were targeted for by i.v. bolus doses followed by i.v. infusions. An isotonic solution of sodium bicarbonate or ammonium chloride was simultaneously infused to study the effect of acid-base imbalance on the clearances. NaCl solution (0.9%) infusion served as a control. Plasma and urine concentrations of methotrexate were quantitated by a sensitive high-performance liquid chromatographic method. Distortion of body acid-base balance did not significantly change the clearances of methotrexate. The results showed that the plasma clearance (4.02 to 4.68 ml/min/kg) of methotrexate was relatively constant over the concentration range studied. The renal and nonrenal clearances, on the other hand, were concentration dependent. As the plasma methotrexate concentration increased from 1 to 20 or 100 micrograms/ml, renal clearance decreased from 3.60 to 4.28 ml/min/kg to 2.62 to 2.73 ml/min/kg, and nonrenal clearance increased form 0.35 to 0.42 ml/min/kg to 1.38 to 1.74 ml/min/kg. Concentration-dependent renal clearance may be due to saturation of the process involving active tubular secretion of methotrexate.
采用多速率输注法，在5只雄性条件性比格杂种犬中研究了甲氨蝶呤的血浆清除率、肾清除率和非肾清除率及其相互关系。通过静脉推注剂量，随后进行静脉输注，将稳态血浆甲氨蝶呤浓度目标设定为1、20和100微克/毫升。同时输注碳酸氢钠或氯化铵等渗溶液，以研究酸碱失衡对清除率的影响。输注0.9%氯化钠溶液作为对照。采用灵敏的高效液相色谱法对甲氨蝶呤的血浆和尿液浓度进行定量。机体酸碱平衡的改变并未显著改变甲氨蝶呤的清除率。结果表明，在所研究的浓度范围内，甲氨蝶呤的血浆清除率（4.02至4.68毫升/分钟/千克）相对恒定。另一方面，肾清除率和非肾清除率与浓度有关。随着血浆甲氨蝶呤浓度从1微克/毫升增加到20或100微克/毫升，肾清除率从3.60至4.28毫升/分钟/千克降至2.62至2.73毫升/分钟/千克，非肾清除率从0.35至0.42毫升/分钟/千克增至1.38至1.74毫升/分钟/千克。浓度依赖性肾清除率可能是由于甲氨蝶呤主动肾小管分泌过程的饱和所致。
