Journal of Toxicological Analysis

Toxicokinetics is that the study of kinetics of absorption, distribution, metabolism, and excretion of a xenobiotic under the conditions of toxicity evaluation. Conventional toxicokinetics uses the hypothetical compartments, and therefore the model consists of rate equations that describe the time course of drug and chemical disposition. The utility of toxicokinetics in toxicity evaluation and interpretation of animal toxicology data is emerging as a crucial tool in product discovery and development. With implementation of the International Conference on Harmonization (ICH) guidelines on systemic exposure and dose selection, toxicokinetics are integrated in routine toxicity evaluations. Although traditional compartmental/noncompartmental models are generally adequate for assessing systemic exposure, they're unable to the predict time course of drug disposition in target tissues and sometimes fail to relate systemic drug levels to a biological response. Physiologically based toxicokinetic (PB-TK) models address this deficiency of traditional compartmental models. PB-TK models are the kinetic models of the uptake and disposition of chemicals supported rates of biochemical reactions, physiological and anatomical characteristics. These models, when developed appropriately, can predict organ drug distribution in several species under sort of conditions. This minireview discusses the essential principles, and applications of traditional compartmental toxicokinetic and physiologically based toxicokinetics (PB-TK) models in drug development and risk assessment. Special emphasis are going to be placed on discussion associated with interpretation of the ICH guidelines associated with toxicokinetics and therefore the utility of toxicokinetics data in dose selection for toxicity and carcinogenicity studies. The utility of PB-TK models in risk assessment of dichloromethane, vinyl chloride, retinoic acid, dioxin, and inhaled organic esters is discussed.