Slørdal L, Sager G, Huseby N E, Aarbakke J
Department of Pharmacology, University of Tromsø, Norway.
J Pharm Pharmacol. 1988 Jan;40(1):50-2. doi: 10.1111/j.2042-7158.1988.tb05149.x.
We have examined the in-vitro distribution of 7-hydroxymethotrexate (7-OH-MTX), a cytotoxic metabolite of methotrexate (MTX), in human blood, and its protein binding in serum. The distribution of 7-OH-MTX (10(-6) M) in fresh samples of whole blood was studied at 37 degrees C and pH 7.51 +/- 0.05 (mean +/- s.d.), and its protein binding was assessed by equilibrium dialysis of serum against Krebs Ringer phosphate buffer at 37 degrees C and pH 7.41 +/- 0.07 (mean +/- s.d.). 7-OH-MTX had a mean cell/plasma concentration ratio of 0.03 (range 0-0.27, n = 18). It was extensively bound in human serum, with a bound fraction of 90.4 +/- 3.3% (mean +/- s.d.) in healthy volunteers (n = 11), and significantly lower, 82.3 +/- 4.0% (mean +/- s.d.), in hypoalbuminaemic surgical patients (n = 7). The binding of 7-OH-MTX was correlated with serum albumin (HSA) concentrations (r = 0.72, P less than 0.0007, n = 18). Blood distribution data support the contention that 7-OH-MTX has a small volume of distribution, and HSA appears to be mainly responsible for the high degree of its protein binding in serum.
我们研究了甲氨蝶呤（MTX）的细胞毒性代谢产物7-羟基甲氨蝶呤（7-OH-MTX）在人血液中的体外分布及其在血清中的蛋白结合情况。在37℃和pH 7.51±0.05（均值±标准差）条件下，研究了7-OH-MTX（10⁻⁶ M）在新鲜全血样本中的分布，并通过在37℃和pH 7.41±0.07（均值±标准差）条件下，将血清与 Krebs Ringer 磷酸盐缓冲液进行平衡透析来评估其蛋白结合情况。7-OH-MTX的平均细胞/血浆浓度比为0.03（范围0 - 0.27，n = 18）。它在人血清中广泛结合，在健康志愿者（n = 11）中的结合分数为90.4±3.3%（均值±标准差），而在低白蛋白血症手术患者（n = 7）中显著降低，为82.3±4.0%（均值±标准差）。7-OH-MTX的结合与血清白蛋白（HSA）浓度相关（r = 0.72，P < 0.0007，n = 18）。血液分布数据支持了7-OH-MTX分布容积较小的观点，并且HSA似乎是其在血清中高度蛋白结合的主要原因。
