Shigetomi Nanami, Kamiya Kenta, Takamori Toru, Yoshimura Naoki, Ozawa Sayaka, Hirono Keiichi, Ichida Fukiko, Taguchi Masato
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama.
Biol Pharm Bull. 2019;42(1):110-115. doi: 10.1248/bpb.b18-00652.
The purpose of this study was to determine the serum protein binding of tadalafil in children with protein-losing enteropathy (PLE) and to evaluate the specific binding of the drug to human serum-derived proteins in vitro. Seventeen serum samples from two PLE patients used after biochemical tests were collected, and the unbound fraction of tadalafil was determined by an ultrafiltration method. The serum albumin concentrations observed in patients #1 and #2 were 2.4-4.2 and 2.9-3.5 g/dL, respectively. The ranges of unbound fraction of tadalafil in patients #1 and #2 were 3.9-13 and 5.0-7.0%, respectively. This suggested that serum albumin was at least a binding carrier for tadalafil because the unbound fraction of tadalafil and serum albumin were slightly correlated. The unbound fraction of tadalafil at the total concentration of 300 ng/mL was negatively dependent on the serum albumin concentration (range: 1.0-5.0 g/dL) in vitro. In the presence of albumin, the additive effect of γ-globulin on the unbound fraction of tadalafil was marginal, but the addition of α-acid glycoprotein to test samples decreased the unbound fraction of the drug. The decrease in the unbound fraction of tadalafil was greater at low albumin levels (2 g/dL). The addition of lipoprotein to test samples also decreased the unbound fraction of tadalafil, suggesting that lipoprotein was also a binding carrier of the drug. These results suggested that the disposition and/or response to tadalafil in PLE patients was altered by the change in protein bindings of the drug.
本研究的目的是测定他达拉非在蛋白丢失性肠病（PLE）患儿中的血清蛋白结合率，并在体外评估该药物与人血清衍生蛋白的特异性结合。收集了两名PLE患者经生化检测后使用的17份血清样本，采用超滤法测定他达拉非的游离分数。患者1和患者2的血清白蛋白浓度分别为2.4 - 4.2 g/dL和2.9 - 3.5 g/dL。患者1和患者2中他达拉非的游离分数范围分别为3.9% - 13%和5.0% - 7.0%。这表明血清白蛋白至少是他达拉非的一种结合载体，因为他达拉非的游离分数与血清白蛋白呈轻度相关。在体外，当总浓度为300 ng/mL时，他达拉非的游离分数与血清白蛋白浓度（范围：1.0 - 5.0 g/dL）呈负相关。在有白蛋白存在的情况下，γ球蛋白对他达拉非游离分数的附加作用很小，但向测试样本中添加α1-酸性糖蛋白可降低该药物的游离分数。在低白蛋白水平（2 g/dL）时，他达拉非游离分数的降低幅度更大。向测试样本中添加脂蛋白也可降低他达拉非的游离分数，这表明脂蛋白也是该药物的一种结合载体。这些结果表明，PLE患者中他达拉非的处置和/或反应因药物蛋白结合的变化而改变。
