The impact of plasma protein binding on toxic plasma drug concentration

Abstract

Drugs with high plasma protein binding are relatively protected from first-pass hepatic metabolism. However, there are concerns about potential problems caused by high plasma protein binding, one of which is toxicity. Statistical analyses of plasma concentration thresholds for toxic and comatose-lethal effects of drugs by multiple linear regression (MLR) models indicate that high plasma protein binding is slightly associated with toxicity of drugs in general, but not in the high (≥90%) plasma protein binding range. Lipophilicity as determined by the octanol/water partition coefficient (Log P) is a major driver of acute toxicity, which can largely and perhaps entirely explain the higher acute toxicity of drugs with high plasma protein binding. Neither plasma protein binding nor lipophilicity have any relation to the therapeutic window of drugs.