Metabolic biotransformations

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. 

Identification of metabolic reactions at an early phase can significantly affect the drug discovery process, because bioavailability, activity, toxicity, distribution and final elimination all depend on metabolic biotransformations [1], Once obtained, this information can help researchers judge whether or not a potential candidate should be eliminated from the pipeline or modified to reduce the affinity for CYP antitarget enzymes. 

Because of the possible effects of active and carrier-mediated processes and metabolic biotransformation, the issue of tissue viability is important for in vitro buccal mucosal experiments. The barrier nature of the buccal mucosa resides in the upper layers of the epithelium, where unlike in the stratum corneum, the cells contain a variety of functional organelles [119, 122, 125, 150], and so tissue viability may be an important component of the barrier function of the tissue. Various methods have been employed to assess the viability of excised buccal mucosa, including measurement of biochemical markers, microscopic methods, and linearity of transport data [42], While biochemical methods, including measurement of adenosine 5 -triphosphate (ATP) levels and utilization of glucose, provide information on the metabolic activity of the tissue, this does not necessarily relate to the barrier function of the tissue. In excised rabbit buccal mucosa, levels of ATP were measured and found to decline by 40% in 6 h, and this correlated well with transmission electron microscopic evaluation of the tissue (intact superficial cells) [32], In addition, the permeability of a model peptide was unaltered up to 6 h postmortem, but at 8 h, a significant change in permeability was observed [32], These investigators therefore claimed that excised rabbit buccal mucosa could be used for diffusion studies for 6 h. 

Intraperitoneal administration of 37.6, 75, or 113 mg 1,2-dibromoethane/kg/day (0.2, 0.4, or 0.6 mmol/kg) to rats resulted in metabolic biotransformation into mercapturic acid which was strongly... 

Metabolism (biotransformation) relates to the enzymatic or nonenzymatic transformation of a substance into a stmcturally different chemical (metabolite). 

Chen Y., J.RN. Rosazza, C.P. Reese, H-Y. Chang, M.A. Nowakowski, and J.P. Kiphnger (1997). Microbial models of soil metabolism Biotransformations of danofloxacin. Journal of Industrial Microbiology and Biotechnology 19 378-384. 

Decreased phase 1 metabolism biotransformation of some drugs... 

Most metabolic biotransformations occur at some point between absorption of the drug into the general circulation and its renal elimination. A few transformations occur in the intestinal lumen or intestinal wall. In general, all of these reactions can be assigned to one of two major categories called phase I and phase II reactions (Figure 4-1). 

The magnitude of diazinon toxicity, like the toxicity of any xenobiotic, is affected by the rate of its metabolic biotransformation to both more and less toxic substances (Klaassen et al. 1986). Therefore, low xenobiotic metabolizing activity could result in greater toxicity. The newborn of several animal species, including humans, have a reduced ability to metabolize xenobiotics and may be more sensitive to diazinon toxicity. 

Amot, J.A., Meylan, W., Tunkel, J., Howard, P.H., Mackay, D., Bonnell, M. and Boethling, R.S. (2009) A quantitative structure-activity relationship for predicting metabolic biotransformation rates for organic chemicals in fish. Environ Toxicol Chem, 28, 1168-1177. 

Introduced mutations affecting drug metabolism allow the study of drug metabolism, biotransformation and eventual undesired toxic side effects. 

Similar to many other cases of biologically active compounds, stereochemistry influences the pharmacological effect of a chiral drug. This can be explained by the fact that there is only one energeticaUy favorable (specific) interaction of an active molecule with its receptor, both being chiral structures. Qualitative and quantitative differences are caused by different receptor affinities as demonstrated in Fig, 1 (1). The metabolism (biotransformation) of drugs is mainly caused by enzymes, which are chiral macromolecules and discriminate between substrate molecules of different stereochemistry, This may result in metabolites of different activity and in different pharmacokinetics, resorption, and excretion. Therefore, racemic drugs should be looked on as a 1 1 mixture of two different compounds. 

Basic pharmacologic principles apply as much to drug interactions as to drug actions. Each kinetic property—absorption, distribution, metabolism (biotransformation), and excretion—is potentially affected by the presence of coadministered medications. Drug interactions follow a variable time-course pattern, from immediate to delayed. Consequently, it is important to remember that several weeks may elapse before the effects of an interactive combination are evident. 

Chemicals that reach the bloodstream by absorption through the gastrointestinal tract will move, via the portal circulation, directly to the liver, where they will normally undergo metabolic biotransformation to more or less active chemical forms, even before they gain access to the various tissues of the body this phenomenon is known as the first-pass effect. 

Table 1 Organs and Organelles Often Associated with Metabolic Biotransformations...

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