Contribution of alpha 1-acid glycoprotein to species difference in lincosamides-plasma protein binding kinetics

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.