Subbarao K, Rucinski B, Rausch M A, Schmid K, Niewiarowski S
J Clin Invest. 1977 Oct;60(4):936-43. doi: 10.1172/JCI108848.
The interactions of dipyridamole with alpha(1) acid glycoprotein of plasma and with human platelets are related to inhibition of adenosine uptake by platelets. Binding studies by equilibrium gel filtration suggested that 1 mol of dipyridamole binds per mol of alpha(1) acid glycoprotein with a dissociation constant of 1.6 muM. Platelets contain two populations of binding sites, one with high and another with lower affinity for the drug. The binding of dipyridamole to the high-affinity sites follows a Michaelis-Menten binding pattern with a dissociation constant of 0.04 muM. Approximately 2 x 10(4) dipyridamole molecules are bound at the high-affinity sites of each platelet. The lower affinity sites bind the drug with a dissociation constant of 4 muM. In the presence of alpha(1) acid glycoprotein of plasma, the binding of dipyridamole to human platelets is inhibited. Correspondingly, the dipyridamole inhibition of adenosine uptake by platelets is reduced 1,000-fold by purified alpha(1) acid glycoprotein. The binding of dipyridamole to human platelets was found to be essential for its inhibition of adenosine uptake by platelets. Dipyridamole decreases the incorporation of [(14)C]adenosine radioactivity in platelet nucleotides and reduces the [(14)C]-ATP to [(14)C]ADP ratio. Purified alpha(1) acid glycoprotein reverses these effects of dipyridamole on adenosine metabolism of platelets in a concentration-dependent manner. An equilibrium of dipyridamole binding to alpha(1) acid glycoprotein and to platelets is proposed.
双嘧达莫与血浆α1酸性糖蛋白及人血小板的相互作用与抑制血小板摄取腺苷有关。平衡凝胶过滤结合研究表明，每摩尔α1酸性糖蛋白结合1摩尔双嘧达莫，解离常数为1.6μM。血小板含有两类结合位点，一类对药物亲和力高，另一类亲和力低。双嘧达莫与高亲和力位点的结合遵循米氏结合模式，解离常数为0.04μM。每个血小板的高亲和力位点大约结合2×10⁴个双嘧达莫分子。低亲和力位点与药物结合的解离常数为4μM。在血浆α1酸性糖蛋白存在的情况下，双嘧达莫与人血小板的结合受到抑制。相应地，纯化的α1酸性糖蛋白可使双嘧达莫对血小板摄取腺苷的抑制作用降低1000倍。发现双嘧达莫与人血小板的结合对其抑制血小板摄取腺苷至关重要。双嘧达莫降低[(¹⁴)C]腺苷放射性掺入血小板核苷酸，并降低[(¹⁴)C]-ATP与[(¹⁴)C] -ADP的比值。纯化的α1酸性糖蛋白以浓度依赖的方式逆转双嘧达莫对血小板腺苷代谢的这些影响。提出了双嘧达莫与α1酸性糖蛋白及血小板结合的平衡关系。
