Conjugation reactions biotransformation

Mirtazapine has a half-life of 20 to 40 hours (319). Its elimination is principally dependent on CYP enzyme-mediated biotransformation as a necessary step. Three CYP enzymes—CYP 1A2, CYP 2D6, and CYP 3A3/4—mediate mirtazapine biotransformation to approximately an equal extent (320). Mirtazapine is also about 25% dependent on elimination by way of a phase II conjugation reaction with glucuronic acid. 

Different enzymatic reactions that occur during the metabolism of chemicals have been well categorized. The biotransformation and conjugation reactions may lead to either the detoxication of the toxicant and the excretion of its metabolites, or to the activation of the toxicant into more reactive intermediates. These may, in turn, react with glutathione, or tissue proteins, or nucleic acids (e.g., RNA, DNA) and undergo different metabolic reactions. 

The second type of conjugation reaction involves the coupling of the endogenous conjugating ligand with a high-energy or reactive xenobiotic. The reactivity associated with the xenobiotic is sometimes the consequence of Phase I biotransformation (e.g., epoxidation, Chapter 10). 

Xenobiotics are biotransformed by phase I enzymes and phase II conjugation reactions to form a variety of metabolites that are generally more water-soluble and less toxic than the parent compound. Occasionally, the enzymic action of phase I or II systems leads to the formation of unstable intermediates or reactive metabolites that are toxic or carcinogenic. Many physiological factors influence the rate of xenobiotic metabolism and the relative importance of different pathways of metabolic activation or detoxication. 

Phase II drug biotransformation involves reaction (conjugation) of a range of functional groups with endogenous compounds (Table 1). The resultant... 

Metabolism includes all of the chemical transformations that occur in living systems. A detailed discussion of metabolism is beyond the scope of this chapter and the reader is directed to other comprehensive resources (22). The lesson to impart to all students interested in green chemical design is that fundamental chemical reactions are the foundation of all of biotransformation. Addition reactions, conjugation reactions, substitutions and eliminations occur to chemicals found naturally inside living systems (biochemistry) and to those that are found external to living systems (xenobiotics) as well as in laboratory round-bottom flasks. Table III lists some of the more common biotransformation pathways. 

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