Sakai T, Hamada T, Awata N, Watanabe J
Pharmaceuticals Research Center, Kanebo, Ltd., Osaka, Japan.
J Pharmacobiodyn. 1988 Apr;11(4):262-7. doi: 10.1248/bpb1978.11.262.
Human, guinea pig and rat sera or plasma protein binding of 1-(2-ethoxyethyl)-2-(hexahydro-4-methyl-1, 4-diazepin-1-yl)benzimidazole difumarate (KG-2413) were investigated by equilibrium dialysis. There were pronounced interspecies differences in binding affinity and binding capacity which were the highest in guinea pig and human species, respectively. In humans, the binding index (n1P1/Kd1) of isolated alpha 1-acid glycoprotein (alpha 1-AG) was seven times higher than that of isolated albumin, and the dissociation constant for human serum at the high affinity binding site was comparable to that for alpha 1-AG. These facts suggested that the free base of KG-2413 was mainly bound to alpha 1-AG in human serum. The contribution of albumin to the binding of KG-2413 in guinea pig and rat plasma may be relatively small. The interspecies differences in KG-2413 binding observed in this study may be due to species differences in the binding affinity and/or capacity of alpha 1-AG.
采用平衡透析法研究了1-(2-乙氧基乙基)-2-(六氢-4-甲基-1,4-二氮杂卓-1-基)苯并咪唑富马酸盐(KG-2413)与人、豚鼠和大鼠血清或血浆蛋白的结合情况。结合亲和力和结合容量存在明显的种间差异，分别在豚鼠和人类中最高。在人类中，分离的α1-酸性糖蛋白(α1-AG)的结合指数(n1P1/Kd1)比分离的白蛋白高7倍，高亲和力结合位点处人血清的解离常数与α1-AG的解离常数相当。这些事实表明，KG-2413的游离碱在人血清中主要与α1-AG结合。白蛋白对豚鼠和大鼠血浆中KG-2413结合的贡献可能相对较小。本研究中观察到的KG-2413结合的种间差异可能是由于α1-AG结合亲和力和/或容量的种间差异所致。
