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.

Pharmacokinetics and molecular detoxication.

The molar concentrations of the catalytic sites of serum cholinesterase (ChE - EC 5.1.1.8.) and cholinesterases (ChEs - acetylcholinesterase (CIChE) -EC 3.1.1.7. and ChE) from brain and perfused liver of male birds, rats, swine and sheep were determined. A positive correlation between the molar concentrations of the catalytic sites of ChEs and the resistance of the animals to some organophosphorus compounds (OPhCs) was found. In addition, the present study also showed that the difference of the molar concentrations of catalytic sites of ChEs in the brain, blood serum and liver can cause varied resistance to some OPhCs.

Correlation between concentration of cholinesterases and the resistance of animals to organophosphorus compounds.

This review continues a general presentation of the principles of stereochemistry with special emphasis on the biomedicinal sciences. Here, we discuss and illustrate the phenomenon of substrate stereoselectivity in biochemistry (endogenous metabolism) and principally in xenobiochemistry or drug metabolism. The review begins with an overview of the stereoselective processes occurring in the biomedicinal sciences. The general rule is for distinct stereoisomers, be they enantiomers or diastereoisomers, to elicit different pharmacological responses (Part 5), to a lesser extent be transported with different efficacies (Part 5), and to be metabolized at different rates (this Part). In other words, biological environments discriminate between stereoisomers both when acting on them and when being acted upon by them. The concept of substrate stereoselectivity describes this phenomenon in endogenous biochemistry and xenobiotic metabolism, as discussed and illustrated in the present Part. The sister concept of product stereoselectivity will be presented in Part 8.

Organic Stereochemistry. Part 7

The detoxification of soman (1,2,2-dimethylpropyl methylphosphonofluoridate) was measured in rat livers, using hemoglobin-free, non-recirculating perfusion in situ.

Detoxification of soman in the perfused rat liver: quantitative uptake and stereoisomer metabolism.

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Detoxification of soman in the perfused rat liver: quantitative uptake and stereoisomer metabolism.