Son D S, Osabe M, Shimoda M, Kokue E
Department of Veterinary Medicine, Tokyo University of Agriculture and Technology, Japan.
J Vet Pharmacol Ther. 1998 Feb;21(1):34-40. doi: 10.1046/j.1365-2885.1998.00111.x.
Protein binding kinetics of lincomycin (LM) and clindamycin (CM) were studied using plasma, albumin and alpha 1-acid glycoprotein (AGP) derived from humans, dogs, cattle and sheep. Based on Rosenthal plots of LM and CM, drug-binding property in plasma presented specific and non-specific binding, except for LM in cattle and sheep and for CM in sheep, where only non-specific binding was demonstrated. Dissociation constant (Kd) and binding capacity (Bmax) for specific binding and proportionality constant (PC) for non-specific binding were as follows: Kd = 3.14 mumol/L, Bmax = 15.28 mumol/L, PC = 0.19 for humans; Kd = 3.84 mumol/L, Bmax = 6.55 mumol/L, PC = 0.14 for dogs; PC = 0.12 for cattle; PC = 0.16 for sheep in LM and Kd = 0.94 mumol/L, Bmax = 12.24 mumol/L, PC = 4.98 for humans; Kd = 1.48 mumol/L, Bmax = 9.52 mumol/L, PC = 2.91 for dogs; Kd = 1.22 mumol/L, Bmax = 4.45 mumol/L, PC = 2.40 for cattle; PC = 1.48 for sheep in CM. The specific binding for each species was different, showing more difference in Bmax compared with Kd. The non-specific binding of LM was similar among species whereas that of CM was different, implying species difference. The drug-binding property of AGP for each species was all specific binding and the Kd was comparable to that obtained from plasma, indicating that AGP is a major specific binder in plasma. The lack of detection of specific binding for LM in cattle and sheep and for CM in sheep plasma could be attributable to a higher Kd and lower plasma AGP concentration compared with other species. The drug-binding property of albumin was characterized as all non-specific, without a great difference among species. Except for CM in sheep, the lower PC in albumin solution compared with that in plasma suggested the presence of another non-specific binder in plasma, i.e. lipoprotein. From the simulation of drug-binding percentage to AGP concentrations, AGP could be a major contributor to drug-plasma protein binding in pathological states. The degree of AGP-drug binding for each species could vary according to the degree of increase of AGP concentrations from a healthy to a pathological state, inducing a decrease in the unbound fraction (fp): 6.1 fold for dogs, 4.6 fold for humans, 1.8 fold for sheep and 1.4 fold for cattle in LM; 5.8 fold for dogs, 5.7 fold for cattle, 4.0 fold for humans and 1.5 fold for sheep in CM. Therefore, the disposition and efficacy of lincosamides affected by fp can be modified differently by the change of fp attributable to the alteration of plasma AGP concentration in each species.
利用源自人类、犬、牛和羊的血浆、白蛋白及α1-酸性糖蛋白（AGP）研究了林可霉素（LM）和克林霉素（CM）的蛋白质结合动力学。根据LM和CM的罗森塔尔图，血浆中的药物结合特性呈现特异性和非特异性结合，但牛和羊的LM以及羊的CM除外，在这些情况下仅表现出非特异性结合。特异性结合的解离常数（Kd）和结合容量（Bmax）以及非特异性结合的比例常数（PC）如下：人类的Kd = 3.14 μmol/L，Bmax = 15.28 μmol/L，PC = 0.19；犬的Kd = 3.84 μmol/L，Bmax = 6.55 μmol/L，PC = 0.14；牛的PC = 0.12；羊的LM的PC = 0.16，人类的CM的Kd = 0.94 μmol/L，Bmax = 12.24 μmol/L，PC = 4.98；犬的CM的Kd = 1.48 μmol/L，Bmax = 9.52 μmol/L，PC = 2.91；牛的CM的Kd = 1.22 μmol/L，Bmax = 4.45 μmol/L，PC = 2.40；羊的CM的PC = 1.48。每个物种的特异性结合不同，与Kd相比，Bmax的差异更大。LM的非特异性结合在物种间相似，而CM的非特异性结合则不同，这意味着存在物种差异。每个物种的AGP的药物结合特性均为特异性结合，且Kd与从血浆中获得的相当，表明AGP是血浆中的主要特异性结合剂。在牛和羊的血浆中未检测到LM的特异性结合以及羊血浆中未检测到CM的特异性结合，这可能归因于与其他物种相比更高的Kd和更低的血浆AGP浓度。白蛋白的药物结合特性被表征为均为非特异性，在物种间没有很大差异。除羊的CM外，白蛋白溶液中的PC低于血浆中的PC，这表明血浆中存在另一种非特异性结合剂，即脂蛋白。通过模拟药物与AGP浓度的结合百分比，AGP可能是病理状态下药物-血浆蛋白结合的主要贡献者。每个物种的AGP-药物结合程度可能会根据AGP浓度从健康状态到病理状态的增加程度而变化，导致游离分数（fp）降低：LM中犬降低6.1倍，人类降低4.6倍，羊降低1.8倍，牛降低1.4倍；CM中犬降低5.8倍，牛降低5.7倍，人类降低4.0倍，羊降低1.5倍。因此，每个物种中血浆AGP浓度的改变导致的fp变化可不同程度地改变受fp影响的林可酰胺类药物的处置和疗效。
