SERUM PROTEIN BINDING OF COCAINE IN MAN

最近使用可卡因的人数有所增加 再加上更有效的剂型的可用性，如 “可卡因”导致与可卡因有关的数量惊人地增加 紧急情况和死亡事件。观察到了广泛的变异性 与可卡因中毒相关的血清浓度。对于其他 基本药物具有相似的性质，药理作用一直 发现与自由比总的关联度更高 药物浓度。这支持了只有药物不能 结合血清蛋白可以跨越生物膜发挥作用 对受体部位的影响。然而，无论可卡因是否 目前还没有与血清蛋白结合的报道。 本申请中提出的研究的目的是充分 评估人体内可卡因与蛋白质结合的程度 血清，评估可饱和结合的潜力，表征 用于这种结合亲和力和容量常数，标识 哪些蛋白质负责可卡因的结合和检测 可卡因代谢物对其蛋白结合的影响。这些 研究将在体外通过添加可卡因和它的 将不同浓度的代谢物转化为分离蛋白溶液 以及从受试者身上获得的血清。蛋白 结合将通过超滤方法进行评估。 初步数据显示，可卡因确实与 血清蛋白和白蛋白、α-1-酸性糖蛋白 两人都牵涉其中。这些数据具有多方面的影响。 因为α-1-酸性糖蛋白浓度变化很大， 在许多情况下会引起炎症性或 免疫反应，可卡因结合的变异性可能 在一定程度上解释了由 给药剂量。此外，这种蛋白质的药物容量很低。 束缚增加了饱和和不成比例的可能性 随着总浓度的增加，自由浓度也会增加。 此外，可卡因及其代谢物之间的竞争 因为结合部位也会导致游离浓度升高 有可能增加急性毒性的可卡因。 建议的研究结果将全面评估这种蛋白质。 可卡因的结合特性，并回答一些问题 与我们对可卡因之间关系的理解有关 行政管理及其影响。

Recent increases in the number of individuals using cocaine coupled with the availability of more potent dosage forms such as "crack" have resulted in an alarming increase in cocaine-related emergencies and fatalities. Wide variability has been observed in serum concentrations associated with cocaine toxicity. For other basic drugs with similar properties, pharmacologic effect has been found to be more highly correlated with free rather than total drug concentration. This supports the principle that only drug not bound to serum proteins can cross biological membranes to exert an effect at receptor sites. However, whether or not cocaine is bound to serum proteins has not been reported. The aims of the studies proposed in this application are to fully assess the extent to which cocaine is protein bound in human serum, evaluate the potential for saturable binding, characterize the affinity and capacity constants for such binding, identify which proteins are responsible for cocaine binding and examine the influence of cocaine metabolites on its protein binding. These studies will be performed in vitro by adding cocaine and its metabolites in varying concentrations to isolated protein solutions as well as to serum obtained from human subjects. Protein binding will be assessed by an ultrafiltration method. Preliminary data suggests that cocaine is indeed highly bound to serum proteins and that albumin and alpha-1-acid glycoprotein are both involved. These data have a number of implications. Because alpha-1-acid glycoprotein concentrations vary widely and are increased in a number of conditions evoking inflammatory or immunologic responses, variability in cocaine binding could partially account for the unpredictability in effect produced by a given dose. In addition, this protein has a low capacity for drug binding raising the possibility of saturation and disproportionate increases in free concentration as total concentration rises. Furthermore, competition between cocaine and its metabolites for binding sites could also result in elevated free concentrations of cocaine with the potential for an increase in acute toxicity. The results of the proposed studies will fully evaluate the protein binding properties of cocaine and answer a number of questions relevant to our understanding of the relationship between cocaine administration and its effects.