Xenobiotic disposition

The previously described equations are characteristic of blood flow rate-limited models it is assumed that xenobiotics cross the cell membrane by simple diffusion and that equilibrium takes place instantaneously between blood and tissue compartments. This assumption is valid for a great number of chemicals. For certain xenobiotics, however, the kinetics of tissue uptake are not consistent with blood flow rate-limited processes since their distribution in a given tissue is limited by the resistance of the cell membrane to the passage of a xenobiotic. In these cases, the basic equation should account for such phenomena to describe adequately the time course of the xenobiotic disposition in the tissue. 

Luecke RH, Wosilait WD, Pearce BA, Young JF. 1997. A computer model and program for xenobiotic disposition during pregnancy. Comput Methods Programs Biomed 53(3) 201-224. 

Anatomical and Physiological Considerations. It is obvious that crustacean species differ considerably from vertebrates in their biological make-up, and that these important differences should be considered in planning xenobiotic disposition studies. 

Although each of these disciplines could be discussed separately, for the contemporary biotransformation scientist these areas are intimately intertwined. Since biotransformations are enzyme mediated, complete understanding of xenobiotic disposition is only achieved when one also considers the role and impact of the individual enzymes involved. 

R Kato, RW Eastbrook, MN Cayen. Xenobiotic Metabolism and Disposition. London Taylor Francis, 1989, p 109. 

Miyamoto, J. 1988. Disposition and metabolism studies of xenobiotics in the environment fundamentals for safety assessment. Jour. Toxicol. Sci. 13 221-246. 

If toxicology can be described as the study of the effects of a chemical on an organism, metabolism can be described as the opposite the effects of the organism on the chemical. Metabolism refers to a process by which a drug (xenobiotic) is chemically modified by an organism. It is part of the overall process of disposition of... 

More than 130 years ago, Keller (1 ) reported the isolation of hippuric acid (benzoylglycine) from the urine of horses fed pure benzoic acid and so ushered in our modern era of metabolism investigations on xenobiotics (foreign substances in the environment). In addition to the valuable basic knowledge of the biological processes of terrestrial animals provided by such studies, the advent of regulations controlling the use of pesticides stimulated research on the disposition of these chemicals by both mammals and insects (2). 

Standardized techniques and equipment for such investigations are in widespread use. Unfortunately, the same cannot be said for metabolism investigations in aquatic animals. Most of the world s animals exclusive of the insects —over 200,000 known species -- live at least a part of their lives in water over 100 species have major economic importance and they form the populations most often at risk of exposure to a growing number of chemical pollutants, but science remains largely ignorant of the disposition of xenobiotics by intact, living specimens of even the most common of the aquatic animals. 

Caldwell, J. (1992) Problems and opportunities in toxicity testing arising from species differences in xenobiotic metabolism. Toxicol. Lett., 64/65, 651-659 Caldwell, J., Anthony, A., Cotgreave, I.A. Sangster, S.A., Sutton, J.D., Bernard, B.K. Ford, R.A. (1985) Influence of dose and sex on the disposition and hepatic effects of cinnamyl anthranilate in the B6C3F1 mouse. Food chem. Toxicol., 23, 559-566 Cattley, R.C., DeLuca, J., Elcombe, C., Fenner-Crisp, R, Lake, B.G, Marsman, D.S., Pastoor,... 

There are many factors, both chemical and biological, which affect the disposition of xenobiotics. Chemical factors include size and structure, pKa, chirality, and lipophilicity. Biological factors include species, sex and strain, genetic factors, hormonal influences, disease and pathological conditions, age, stress, diet, dose, enzyme induction and inhibition, and tissue and organ specificity. All of these factors can affect the toxicity of a chemical by changing its disposition, especially its metabolism. 

The hydrolysis of esters by esterases and of amides by amidases constitutes one of the most common enzymatic reactions of xenobiotics in humans and other animal species. Because both the number of enzymes involved in hydrolytic attack and the number of substrates for them is large, it is not surprising to observe interspecific differences in the disposition of xenobiotics due to variations in these enzymes. In mammals the presence of carboxylesterase that hydrolyzes malathion but is generally absent in insects explains the remarkable selectivity of this insecticide. As with esters, wide differences exist between species in the rates of hydrolysis of various amides in vivo. Fluoracetamide is less toxic to mice than to the American cockroach. This is explained by the faster release of the toxic fluoroacetate in insects as compared with mice. The insecticide dimethoate is susceptible to the attack of both esterases and amidases, yielding nontoxic products. In the rat and mouse, both reactions occur, whereas sheep liver contains only the amidases and that of guinea pig only the esterase. The relative rates of these degradative enzymes in insects are very low as compared with those of mammals, however, and this correlates well with the high selectivity of dimethoate. 

Bimbaum, L.S. (1985) The role of structure in the disposition of halogenated aromatic xenobiotics. Environ. Health Perspectives 61, 11-20. 

Illing, H.P.A., Ed., Xenobiotic Metabolism and Disposition, CRC Press, Boca Raton, FL, 1989. 

Utilize rats, sheep, and/or cattle to study the disposition of selected xenobiotics such as 2,3,7,8-TCDD and protocols that might enhance tolerance... 

The Influence of Fermentable Dietary Fiber on the Disposition and Toxicity of Xenobiotics... 

Our first indication that fermentable fiber could alter microfloral metabolism was based on studies assessing the influence of dietary fiber types on the disposition of model xenobiotics using pharmacokinetic analysis (14). Amaranth was selected as a model xenobiotic for these studies because it was absorbed only after reduction by gut microflora (15). 

---