Authors: Andreas Svennebring
Addresses: Department of Pharmaceutical Biosciences, Division of Pharmaceutical Bioinformatics, Biomedical Centre, Box 591, Uppsala University, SE 751 24, Uppsala, Sweden
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.
Keywords: acute toxicity; ADME; distribution; disposition; free fraction; plasma concentration; plasma protein binding; toxic plasma drug concentration; multiple linear regression; MLR; lipophilicity.
International Journal of Computational Biology and Drug Design, 2016 Vol.9 No.4, pp.345 - 368
Received: 15 Oct 2015
Accepted: 12 Apr 2016
Published online: 28 Oct 2016 *