Pharmacokinetics and molecular detoxication.
This paper presents a comprehensive overview of the pharmacokinetic parameters used from in vivo and in vitro studies that are important in order to understand the major conceptual approaches of toxicokinetics and the disposition of environmental chemicals. In vitro biochemical information concerning the detoxication of environmental chemicals is also presented. The discussion leads to a more complete appreciation for the use of in vitro measurements for in vivo correlations. The concept of interspecies scaling in the interpolation and extrapolation of fundamental biochemical metabolic processes is illustrated with a number of examples. Additional examples of in vitro-in vivo correlations are presented in the evaluation of the impact of chemical exposure to humans. Finally, several important metabolic detoxication enzymes are presented, including the mammalian microsomal cytochrome P450 and flavin-containing monooxygenases as well as carboxylesterases and glucuronosyltransferases, to provide insight into the processes of chemical detoxication in mammalian tissue and blood. Because interspecies scaling and the pharmacokinetics of chemical disposition have already shown their usefulness in understanding some examples of chemical disposition, our summary focuses on showing the usefulness of the pharmacokinetic equations and providing confidence in using the approach for in vitro-in vivo correlations. Ultimately, the presentation may provide the reader with a conceptual framework for future evaluation of the human health risks associated with environmental toxicants.
Cashman
J R
JR
Seattle Biomedical Research Institute, Washington 98109, USA.
Perotti
B Y
BY
Berkman
C E
CE
Lin
J
J
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004785:Environmental Pollutants / Q000493:pharmacokinetics*; D006801:Humans; D008658:Inactivation, Metabolic; D007306:Insecticides / Q000493:pharmacokinetics; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D009538:Nicotine / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds; D018570:Risk Assessment
D004785:Environmental Pollutants; D007306:Insecticides; D009943:Organophosphorus Compounds; D009538:Nicotine; D003577:Cytochrome P-450 Enzyme System; D002265:Carboxylic Ester Hydrolases