Protein binding of cocaine in human serum

The protein binding characteristics of cocaine have not been extensively studied. Since cocaine is related to other local anesthetic compounds which are highly protein bound, we examined the binding of cocaine in human serum using an ultrafiltration method. The free fraction averaged 0.083 +/- 0.018 in the serum of 12 healthy volunteers. Binding was studied at concentrations ranging from 0.1 to 500 micrograms/ml and was concentration dependent, with increases being most pronounced at concentrations above 5 micrograms/ml. Two classes of binding sites were identified with affinity and capacity constants consistent with binding to alpha-1-acid glycoprotein (AAG) and albumin. The addition of AAG to serum resulted in a decrease in the free fraction from 0.079 to 0.041, while tris(butoxyethyl)phosphate increased the free fraction to 0.233. The binding ratio was found to be highly correlated with the AAG concentration (r = 0.89). In addition, the predicted free fraction in the absence of AAG (0.67) was in good agreement with the observed value of 0.647 in a solution of human serum albumin (4.5 g/dl). Of the metabolites of cocaine, only norcocaine displaced the parent drug from serum binding sites. These results indicate that cocaine is highly bound to serum proteins, primarily albumin and AAG. The significance of concentration-dependent binding to cocaine toxicity remains to be established.