Multiple human serum binding of two thienopyridinic derivatives,ticlopidine and PCR 2362, and their distribution between HSA, α1-acid glycoprotein and lipoproteins

The binding of two drugs, ticlopidine and PCR 2362, chemically related to thienopyridin, potent antiaggregant agents, was studied in vitro to serum and to the corresponding isolated proteins, HSA, α₁-AGP, VLDL, LDL and HDL, using equilibrium dialysis at pH 7.4 and 37°. The binding of these drugs to HSA and lipoproteins was non-saturable. The binding capacity of the lipoproteins was much greater than that of HSA and appeared to be dependent on lipid content. The binding capacities of the apoproteins were less than 10% of that observed for the native lipoproteins suggesting that drug-lipoprotein binding involves drug solubilisation in the lipid phase of lipoproteins rather than a classical binding to definite sites. However drug binding to α₁-AGP was saturable with n = 3 for both and K = 89,000 and 33,000 for ticlopidine and PCR 2362, respectively. At physiological concentration, α₁-AGP binding capacity represented 15% of total serum binding capacity which could double in pathological states, in which the level of this protein is increased.