Mammalian drug metabolism

O. Corcoran, J.C. Lindon, R. Hall, I.M. Ismail, J.K. Nicholson, The potential of F-19 NMR spectroscopy for rapid screening of cell cultures for models of mammalian drug metabolism. Analyst 126 (2001) 2103-2106. 

Metabolism studies are essential for approval of any clinically useful drug. Microorganisms have been successfully used as in vitro models for prediction of mammalian drug metabolism due to the significant similarity of certain microbial enzyme systems, specifically fungi, with mammalian liver enzyme systems.66 The following metabolism study represents the first for a cembranoid diterpene and may aid future development of other cembranoids as clinically useful drugs. 

Griffiths, D.A., Best, D.J., Jezequel, S.G. The screening of selected microorganisms for use as models of mammalian drug metabolism. Appl. Microbiol. Biotechnol. 1991, 35 373-381. 

NDMA is mutagenic for Escherichia coli, Salmonella typhimurium, and Neurospora crassa. It can produce mitotic recombination in Sacharoyus cerevesiae species, recessive lethal mutations in Drosophilla melanogaster, and chromosomal aberrations in mammalian cells. Mutagenic responses in bacterial cells are dependent upon the addition of a mammalian drug metabolism system (specific form of cytochrome P450). 

Talafous J, Sayre LM, Mieyal JJ, Klopman G. META. 2. A dictionary model of mammalian xenobiotic metabolism. J Chem Inf Comput Sci 1994 34 1326-33. Klopman G, Tu M, Talafous J. META. 3. A genetic algorithm for metabolic transform priorities optimization. J Chem Inf Comput Sci 1997 37 329-34. Langowski J, Long A. Computer systems for the prediction of xenobiotic metabolism. Adv Drug Del Rev 2002 54 407-15. 

In the 1970s, Smith and Rosazza introduced the concept of microbial models of mammalian metabolism [38,39]. Two reviews in this area were published in 1999 [40,41]. Since these, there have been numerous reports describing the use of microbial biotransformation in drug metabolism studies [42-54]. These reports demonstrated that microbial enzymes were able to... 

Zmijewski, M., Gillespie, T.A., Jackson, D.A. etal. (2006) Application of biocatalysis to drug metabolism preparation of mammalian metabolites of a biaryl-bis-sulfonamide AMPA (a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor potentiator using Actinoplanes missouriensis. Drug Metabolism and Disposition The Biological Fate of Chemicals, 34, 925—931. 

Rao, G.P. and Davis, P.J. (1997) Microbial models of mammalian metabolism biotransformation of HP 749 (besipirdine) using Cunninghamella elegans. Drug Metabolism and Disposition The Biological Fate of Chemicals, 25, 709-715. 

Canned, R.J., Knaggs, A.R., Dawson, M.J. et al. (1995) Microbial biotransformation of the angiotensin II antagonist GR117289 by Streptomyces rimosus to identify a mammalian metabolite. Drug Metabolism and Disposition The Biological Fate of Chemicals, 23, 724—729. 

Drugs can be metabolized either in the intestinal lumen or in the intestinal wall. The most common approach to determine drug metabolism in the intestinal lumen is by direct incubation with bacterial preparations, which can be gut content or pure culture of organisms of the GI tract of various mammalian species [62],... 

Teissier E, Fennrich S, Strazielle N, Daval JL, Ray D, et al. 1998. Drug metabolism in in vitro organotypic and cellular models of mammalian central nervous system activities of membrane-bound epoxide hydrolase and NADPH-cytochrome P-450 (c) reductase. Neurotoxicology 19 347-355. 

Ketoconazole Blocks fungal P450 enzymes and interferes with ergosterol synthesis Poorly selective interferes with mammalian P450 function Broad spectrum but toxicity restricts use to topical therapy Oral, topical Toxicity and interactions Interferes with steroid hormone synthesis and phase I drug metabolism... 

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