Toxicity and Metabolism

A. M. ter laak, N. P. E. Vermeulen, Molecular-modeling approaches to predict metabolism and toxicity, in Pharmacokinetic Optimization in Drug Research, B. Testa, H. van de Water-beemd, G. Folkers, R. Guy (Eds.), Wiley-VCH, Weinheim, 2001,... 

Bugrim A, Nikolskaya T, Nikolsky Y. Early prediction of drug metabolism and toxicity systems biology approach and modeling. Drug Discov Today 2004 9 127-35. 

Yang CS, Brady JF, Hong JY Dietary effects on cytochromes P450, xenobiotic metabolism, and toxicity. FASEB J 1992 6 737. 

StarekA. 1991. [The effect of trichloroethylene on the metabolism and toxicity of benzene in rats.] Folia Medica Cracoviensia 32 169-184. (Polish)... 

Cerniglia CE, IP Ereeman, JR Althans, C van Baalen (1983) Metabolism and toxicity of 1- and 2-methylnaph-thalene and their derivatives in cyanobacteria. Arch Microbiol 136 177-183. 

Monks, T. J. Jones, D. C. The metabolism and toxicity of quinones, quinonimines, quinone methides, and quinone-thioethers. Curr. Drug Metab. 2002, 3, 425M-38. 

Preclinical drug development also involves animal testing [61]. Data from one rodent species and one nonrodent species are usually collected to determine the absorption, metabolism, and toxicity characteristics of the compound. Both short-term (2 weeks to 3 months) and long-term (up to several years) studies are done. The long-term studies are particularly useful for... 

Kostial K, Kello D, Jugo S. et al. 1978. Influence of age on metal metabolism and toxicity. Environ Health Perspect 25 81-86. 

The Danish (Q)SAR database is a repository of estimates from over 70 [28] (Q)SAR models for 166,072 chemicals. The (Q)SAR models encompass endpoints for physicochemical properties, fate, ecotoxicity, absorption, metabolism, and toxicity... 

Price and Fletcher [139] studied the metabolism and toxicity of primaquine in human and monkeys. Results of a number of studies by the authors on primaquine... 

Yu, XZ, Gu J-D (2006) Uptake, metabolism, and toxicity of methyl ter/-butyl ether (MTBE) in weeping willows. J Hardz Mat B137 1417-1423 Yu, XZ, Gu J-D (2007a) Differences in Michaelis-Menten kinetics for different cultivars of maize during cyanide removal. Ecotoxicol Environ Saf 67 254-259... 

Zinc interacts with numerous chemicals, sometimes producing greatly different patterns of accumulation, metabolism, and toxicity when compared to zinc alone. Recognition of these interactions is essential to the understanding of zinc kinetics in the environment. 

The literature emphasizes that arsenic metabolism and toxicity vary greatly between species and that its effects are significantly altered by numerous physical, chemical, and biological modifiers. Adverse health effects, for example, may involve respiratory, gastrointestinal, cardiovascular, and hematopoietic systems, and may range from reversible effects to cancer and death, depending partly on the physical and chemical forms of arsenic tested, the route of administration, and the dose. 

Miyamoto J (1976) Degradation, metabolism and toxicity of synthetic pyrethroids. Environ Health Perspect 14 15-28... 

Kaneko H (2011) Pyrethroids mammalian metabolism and toxicity. J Agric Food Chem 59 2786-2791... 

Holme, J. (1985). Xenobiotic metabolism and toxicity in primary monolayer cultures of... 

Stereoisomerism will influence metabolism and toxicity. For example, Lu et al. (1998) reported a comparison of (5)-(—jlfosfamide and (i )-(+)-Ifsosfamide. They demonstrated that there were significant differences between the two stereoisomers with regard to pharmacokinetic behavior and major metabolite formation, as shown in Table 18.13. 

Blakley RL, Coop IE. 1949. The metabolism and toxicity of cyanides and cyanogenic blycosides in sheep. II. Detoxication of hydorcyanic acid. N.Z.J. Sci. Technol. 31A(3) 1-16. 

Bennington JL, ed. 1978. Pathology of peripheral nerve Chapter 4. Metabolic and toxic polyneuropathies. Major Probl Pathol 9 72-95. 

Conjugation-Deconjugation Reactions in Drug Metabolism and Toxicity , Ed. F. C. Kauffman, Springer Verlag, Berlin, 1994. 

L. W. Wormhoudt, J. N. Commandeur, N. P. Vermeulen, Genetic Polymorphisms of Human V-Acetyltransferase, Cytochrome P450, Glutathione 5-Transferase, and Epoxide Hydrolase Enzymes Relevance to Xenobiotic Metabolism and Toxicity , Crit. Rev. Toxicol. 1999, 29, 59 - 124. 

J. L. Nieusma, D. J. Claffey, C. Manigher-Poulet, T. Imiolczyk, D. Ross, J. A. Ruth, Stereochemical Aspects of 1,3-Butadiene Metabolism and Toxicity in Rat and Mouse Liver Microsomes and Freshly Isolated Rat Hepatocytes , Chem. Res. Toxicol. 1997,10, 450 - 456. 

T. Watabe, N. Ozawa, A. Hiratsuka, Studies on Metabolism and Toxicity of Styrene. VI. Regioselectivity in Glutathione 5-Conjugation and Hydrolysis of Racemic, R- and S-Phenyloxiranes in Rat Liver , Biochem. Pharmacol. 1983, 32, 111 - 785. 

In vitro assays are increasingly being used. Some of the reasons are cost, availability of more rapid results, and avoidance of negative publicity. Assays such as cytochrome P-450 enzymes, the Ames test, and the mouse lymphoma tk test are in vitro methods. For absorption studies, Caco-2 (Exhibit 5.9) and Madin-Darby canine kidney cell assays are now routinely used. Hepatocyte cell lines with metabolism capacity are being developed to test drug metabolism and toxicity. All these examples show that, where possible, pharmaceutical firms are gradually dispensing with animal studies. 

White RD, Gandolfi AJ, Bowden GT, et al. 1983. Deuterium isotope effect on the metabolism and toxicity of 1,2-dibromoethane. Toxicol AppI Pharmacol 69 170-178. 

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