SERUM PROTEIN BINDING OF COCAINE IN MAN

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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.