Distribution of chlorpromazine in a simplified blood influenced by various drugs

Summary

The binding of chlorpromazine to erythrocytes and to albumin as influenced by other drugs was studied in a simplified blood (31.5±0.3% bovine erythrocytes, 4 g-% bovine serum albumin in 0.02 M phosphate buffer solution containing 0.15 M NaCl). the total concentration of chlorpromazine in the simplified blood was 10⁻⁴ M, the concentration of the displacing drugs was 10⁻³ M. After an incubation period of 3 h at 22° C the chlorpromazine concentration was determined in the albumin solution after centrifugation of the blood at 3000×g and in the aqueous phase after ultracentrifugation at 150000×g. Under control conditions 68.1±0.9% of chlorpromazine was bound to the erythrocytes, 28.5±0.9% was bound to albumin and 3.5±0.2% was free in the aqueous phase.

The following substances were tested for their ability to alter the distribution of chlorpromazine in the simplified blood: Azetazolamide, amitriptyline, chlorimipramine, chlorothiazide, chlortetracycline, desoxycholic acid, diphenylhydantoin, imipramine, indomethacin, ioglycamic acid, oleic acid, oxytetracycline, phenindamine, phenprocoumon, phenylbutazone, probenecid, quinine sulfate, salicylic acid, stearic acid, sulfisoxazole, sulfamethoxypyridazine, suramin, tetracycline, thiopental. In most cases chlorpromazine shifted considerably between erythrocytes and albumin whereas the unbound fraction was not markedly changed.

The effect of some of these drugs on the binding of chlorpromazine was also investigated in an albumin solution without erythrocytes. Evidence is presented that the binding capacity of albumin may be fundamentally changed when erythrocytes are present. It is concluded that binding studies merely with albumin solutions, plasma or serum may be misleading when pharmacokinetic implications are argued.