Evaluation of toxicokinetic interactions mediated by plasma protein binding during amoxapine intoxication

Abstract

Toxicity enhancement mediated by plasma protein binding during intoxication remains poorly understood. It is known that in mice, brain penetration of amoxapine (AMX) increases nonlinearly with increasing doses; therefore, this study investigated its potential to enhance toxicity via plasma protein binding. AMX was added to mouse or human plasma and adjusted to therapeutic, toxic, and lethal concentrations. The plasma protein-binding ratio and free AMX concentration were measured using ultrafiltration and equilibrium dialysis. Furthermore, the binding ratios of varying concentrations of chlorpromazine, which is often co-administered with AMX in cases of overdose, was analyzed in the presence of therapeutic AMX concentrations. The binding ratio of AMX exceeded 90%, thereby demonstrating a high binding rate; however, this ratio was lower in human plasma than in mice. A nonlinear increase in free AMX concentration was observed in mouse plasma, particularly at high concentrations. In contrast, free AMX concentration showed a linear increase in human plasma. Neither the therapeutic nor toxic concentration of chlorpromazine produced any visible effects on the plasma protein binding ratio or the free AMX concentration. These results suggest that protein binding of AMX is more readily saturated in mouse plasma than in human plasma. In addition, chlorpromazine inhibits AMX binding to α₁-acid glycoprotein; however, AMX may alternatively binds to albumin, which results in no apparent change in the total binding ratio. Further insights into the toxicokinetic interactions mediated by plasma protein binding are also needed for various toxic substances other than AMX.